potassium-competitive acid blockade: a new therapeutic...

www.elsevier.com/locate/pharmthera

Pharmacology & Therapeutic

Associate editor: G.J. Sanger

Potassium-competitive acid blockade: a new therapeutic

strategy in acid-related diseases

Kjell Andersson *, Enar Carlsson

AstraZeneca R&D, 431 83 Mölndal, Sweden

Abstract

Current therapies to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and other acid-related diseases either

prevent stimulation of the parietal cell (H2 receptor antagonists, H2RAs) or inhibit gastric H+,K+-ATPase (e.g., proton pump inhibitors, PPIs).

Of the 2 approaches, the inhibition of the final step in acid production by PPIs provides more effective relief of symptoms and healing.

Despite the documented efficacy of the PPIs, therapeutic doses have a gradual onset of effect and do not provide complete symptom relief in

all patients. There is scope for further improvements in acid suppressive therapy to maximize healing and offer more complete symptom

relief. It is unlikely that cholecystokinin2 (CCK2, gastrin) receptor antagonists, a class in clinical trials, will be superior to H2RAs or PPIs.

However, a new class of acid suppressant, the potassium-competitive acid blockers (P-CABs), is undergoing clinical trials in GERD and

other acid-related diseases. These drugs block gastric H+,K+-ATPase by reversible and K+-competitive ionic binding. After oral doses,

P-CABs rapidly achieve high plasma concentrations and have linear, dose-dependent pharmacokinetics. The pharmacodynamic properties

reflect the pharmacokinetics of this group (i.e., the effect on acid secretion is correlated with plasma concentrations). These agents dose

dependently inhibit gastric acid secretion with a fast onset of action and have similar effects after single and repeated doses (i.e., full effect

from the first dose). Animal studies comparing P-CABs with PPIs suggest some important pharmacodynamic differences (e.g., faster and

better control of 24-hr intragastric acidity). Studies in humans comparing PPIs with P-CABs will help to define the place of this new class in

the management of acid-related diseases.

D 2005 Elsevier Inc. All rights reserved.

Keywords: Gastroesophageal reflux; Peptic ulcer disease; Potassium-competitive acid blocker; Proton pump inhibitor

Abbreviations: CCK, cholecystokinin; cyclic AMP, cyclic adenosine monophosphate; ECL, enterochromaffin-like cell; GERD, gastroesophageal reflux

disease; H2RA, histamine H2 receptor antagonist; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor.

Contents

0163-7258/$ - see fro

doi:10.1016/j.pharmth

* Corresponding aut

E-mail address: k

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

2. Physiology of acid secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

3. Structure and properties of gastric H+,K+-ATPase . . . . . . . . . . . . . . . . . . 296

4. Targeting gastric acid secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

4.1. H2 receptor antagonists and H3 receptor agonists . . . . . . . . . . . . . . 297

4.2. Muscarinics and cholecystokinin2 receptor antagonists . . . . . . . . . . . . 297

4.3. Proton pump inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

5. Potassium-competitive acid blockers. . . . . . . . . . . . . . . . . . . . . . . . . 299

5.1. Development of the potassium-competitive acid blocker class . . . . . . . . 299

5.2. Mechanism of potassium-competitive acid blocker inhibition of gastric

H+,K+-ATPase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

5.3. Selectivity of potassium-competitive acid blockers for gastric H+,K+-ATPase . 301

nt matter D 2005 Elsevier Inc. All rights reserved.

era.2005.05.005

hor. Integrative Pharmacology, AstraZeneca R&D, Mölndal, Sweden.

[email protected] (K. Andersson).

s 108 (2005) 294 – 307

K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307 295

5.4. Pharmacokinetics of potassium-competitive acid blockers . . . . . . . . . . 301

5.5. Pharmacodynamics of potassium-competitive acid blockers . . . . . . . . . 302

5.6. Pharmacodynamic comparisons of potassium-competitive acid blockers with

other agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

1. Introduction

By the 19th century, gastric acid was known to be

important in many physiological processes, such as protein

digestion and the absorption of calcium and iron. Alongside

these functions, sterilization of food is now also recognized

as a vital function of gastric acid. Over time, awareness of

its central role in the etiology of peptic ulcer disease (PUD),

and more recently, gastroesophageal reflux disease (GERD),

has also grown. This knowledge, together with an increased

understanding of the physiology of acid production, directed

the search for therapies in these diseases through inhibition

of gastric acid secretion. However, until just under 30 years

ago, patients with acid-related diseases had to rely on

antacids, atropine, and other interventions (e.g., behavioral)

for the relief of symptoms. The treatment of PUD was

challenging and, apart from surgery, employed largely

ineffective approaches that included a bland diet, antacids,

and anticholinergics. Although antacids, and other

approaches such as dietary changes and sucralfate, provide

a degree of relief from the symptoms of GERD, healing of

erosions was very difficult to achieve except with high and

frequent doses of antacids (Grove et al., 1985).

The emergence of H2 receptor antagonists (H2RAs) in

the 1970s represented the first major advance in the

treatment of GERD and PUD, as they provided better

symptom control and allowed higher healing rates

compared with antacids. However, these agents have a

relatively short duration of action, their effect is dimin-

ished by meal-stimulated secretion, and tolerance to their

antisecretory effect can develop. Other approaches used to

treat GERD (e.g., prokinetics, sucralfate) have generally

not met expectations.

The first proton pump inhibitor (PPI), omeprazole, was

approved for use in 1988 (Lindberg et al., 1990) and was the

forerunner of a more effective class of agents than H2RAs.

PPIs provide superior symptom relief and achieve higher

healing rates in GERD and PUD than do H2RAs (Chiba et

al., 1997; van Pinxteren et al., 2001; Salas et al., 2002).

Despite the undoubted efficacy of PPIs, there are still areas

in which they could be improved upon (e.g., faster and

better symptom control and more rapid healing). The quest

for better therapy has driven research into other acid-

suppressive treatments. This review examines the develop-

ment and properties of current and potential treatments to

suppress acid production, with particular emphasis on the

potassium-competitive acid blocker (P-CAB) class.

2. Physiology of acid secretion

Hydrochloric acid (HCl) is secreted into the lumen of the

stomach by parietal cells in the glands of the oxyntic

mucosa. Gastric H+,K+-ATPase is fundamental to this

process of acid secretion. This enzyme, located in the apical

membrane of the parietal cell, transports H+ into the parietal

cell canaliculus in exchange for K+. The secretion of H+ is

accompanied by the passage of Cl� across the apical

membrane into the canaliculus, which ensures that acid

secretion is electroneutral. For each H+ ion that is moved

into the canaliculus by the action of the H+,K+-ATPase, a

HCO3� ion is moved out of the parietal cell cytoplasm by a

basolateral Cl�/HCO3� exchanger that also delivers a Cl�

ion into the cytosol. Cl� is secreted into the canaliculus via

Cl� channels in the apical membrane of the parietal cell. It is

possible that more than 1 type of Cl� channel is involved in

the movement of Cl� across the membrane, but currently,

there is evidence only for the ClC-2 channel (Malinowska et

al., 1995).

The exchange of H+ for K+ requires a relatively high

level of K+ in the parietal cell canaliculus. There is evidence

that K+ transported into the cytoplasm by the enzyme is

recycled and returns to the canaliculus via specific K+

channels in the apical membrane of the cell. To date, 3

different types of K+ channels (KCNQ1, Kir2.1, and Kir4.1)

with properties consistent with a role in acid secretion have

been identified in animals (Dedek & Waldegger, 2001;

Grahammer et al., 2001; Fujita et al., 2002; Lambrecht et al.,

2004; Malinowska et al., 2004). It is uncertain what the

counterpart(s) of these channels may be in humans.

Production of gastric acid by the parietal cell is a tightly

regulated process and is triggered by physiological stim-

ulation of receptors located on the basolateral membrane of

the cell. The stimuli include histamine, gastrin, and

acetylcholine, each of which binds to a specific receptor.

This ligand–receptor interaction involves an elevation of

intracellular calcium and/or cyclic adenosine monophos-

phate (cyclic AMP) as part of the signal transduction

pathways. Activation of these pathways result in morpho-

logical and ultrastructural changes that lead to the inclusion

of the gastric H+,K+-ATPase into the apical membrane of the

cell and, ultimately, acid secretion.

In the cytoplasmic space of the unstimulated parietal cell

are tubulovesicles, which contain the gastric H+,K+-ATPase.

The apical membrane of the parietal cell has canaliculi that

invaginate from its surface and in the resting cell that are

K. Andersson, E. Carlsson / Pharmacology & Therapeutics 108 (2005) 294–307296

lined with short microvilli. When the cell is stimulated, the

microvilli on the apical membrane elongate, the canalicular

spaces enlarge, and the number of tubulovesicles decreases.

It is generally agreed that the tubulovesicular membrane

fuses with the apical plasma membrane (Forte & Yao, 1996;

Duman et al., 2002). Prior to stimulation of the cell, the

H+,K+-ATPase is inactive due to the low permeability of the

tubulovesicular membranes to K+ (Reenstra & Forte, 1990).

The enzyme does not appear to undergo any chemical

modification on membrane fusion (Dunbar & Caplan,

2001), but its consequent placement near to K+ and Cl�

channels, together with the availability of K+ in the

canaliculus, provides the necessary environment to allow

ATP-driven secretion of HCl (Forte & Yao, 1996).

The concentration of H+ in the parietal cell canaliculi

results in a pH of 1.0 or less, compared with a pH of 7.4 in

the blood and parietal cell cytoplasm. To be able to create

such a pH gradient requires a lot of energy (e.g., ATP),

hence the parietal cell is the most mitochondria-rich cell in

the body. The pH in the canaliculi is much lower than that in

other acidic compartments such as lysosomes, endosomes,

and chromaffin granules. In these locations, the pH ranges

from 4.5 to 6.5 (Futai et al., 2000). Gastric H+,K+-ATPase

has been suggested to be present at sites other than the

stomach (e.g., the cortical collecting duct of the kidney;

[Kraut et al., 2001], rat vascular smooth muscle cells

[McCabe & Young, 1992], human leucocytes [Ritter et al.,

1998], and rat cardiac myocytes [Beisvag et al., 2003]). The

enzymes at these locations do not generate a very low pH,

but probably contribute to acid–base and potassium homeo-

stasis (van Driel & Callaghan, 1995; Sangan et al., 1997;

Kraut et al., 2001). Other H+,K+-ATPase isoforms have been

reported to occur in various cells (e.g., in the colon;

Rajendran et al., 1998). For a discussion of the selectivity

of P-CABs for gastric H+,K+-ATPase, see Section 5.3.

3. Structure and properties of gastric H+,K+-ATPase

The gastric H+,K+-ATPase is an a/h heterodimer, witheach subunit having distinct functions. The a subunit, whichhas 10 helical transmembrane segments (M1–M10), is

responsible for the catalytic activity of the enzyme and

contains sites for ATP binding, as well as the cation (K+ and

H+) binding site. The latter binding site is located near the

middle of the membrane domains in the a subunit (Munsonet al., 2000). It appears to be formed by amino acid residues

from M4, M5, and M6, with the ion being held in place by 6

oxygen atoms provided by these residues (Koenderink et al.,

2004). The h subunit has a single transmembrane domain.The subunit is required for the functional expression of the

enzyme.

The exchange of H+ for K+ involves conformational

changes in the tertiary structure of gastric H+,K+-ATPase

(Vander Stricht et al., 2001). According to the Post-Albers

model, there are 2 important conformational states. In the E1

form, the ion-binding site faces the parietal cell cytoplasm

and has high affinity for H+ but low affinity for K+. In the E2form, the ion-binding site faces the extracellular lumen with

low affinity for H+ and high affinity for K+. The relative

affinity of the 2 forms for K+ may be determined by

differences between the E1 and E2 forms in the topography

of the K+ ion binding site or in the path through which the

ion accesses its binding site (Vagin et al., 2003). The K+

affinity is also influenced by a salt bridge from M5 to M6

that exists only when the enzyme is in the E2 form

(Koenderink et al., 2004).

H+ binds to the cytoplasmic face of the enzyme when it

is in the E1 form. The E1 form also binds ATP from the

cytoplasm to form a phosphoenzyme (E1P), which

provides the energy for the change to the (phosphorylated)

E2 form of the enzyme. The conformational shift causes

the translocation of H+ from the parietal cell cytoplasm

into the canaliculus. The phosphorylated E2 form binds K+

from the canaliculus. This ion is necessary for the

subsequent dephosphorylation of the H+,K+-ATPase

(Rabon et al., 1993). In particular, K+ appears to affect

the conformation of a large loop in which there is a

phosphorylation domain, and it is involved in stabilizing a

hairpin between M5 and M6 that appears to be involved in

linking ATP hydrolysis to cation transport (Swarts et al.,

1998; Gatto et al., 1999). When K+ occupies the cation

binding site, it may activate the enzyme by neutralizing a

negative charge (or charges) that inhibit the dephosphor-

ylation reaction (Swarts et al., 1998; Hermsen et al., 2000).

Upon dephosphorylation, the conformation of the enzyme

returns to the E1 form in which the binding site is again

exposed to the cytoplasm. The enzyme then releases K+

into the parietal cell cytoplasm. Thus, K+ is not only the

counterion for H+, but is also essential for the catalytic

cycle of gastric H+,K+-ATPase.

4. Targeting gastric acid secretion

The treatment of peptic ulcer disease (PUD) has been

based on Karl Schwartz’s dictum of Fno acid, no ulcer_.Although recent advances in our understanding have high-

lighted the multifactorial pathogenesis of both PUD and

GERD, gastric acid is still recognized as a central

component in both diseases. There is a correlation between

healing of GERD lesions and the proportion of time (over

24 hr) when intragastric pH is greater than 4 (Bell et al.,

1992). Furthermore, the period during which esophageal pH

is less than 4 increases on moving from endoscopy-negative

GERD patients to patients with worsening grades of

esophagitis (Fiorucci et al., 1992). Therapeutically, the

degree of acid suppression and its relationship with a

positive outcome (e.g., symptom relief, healing) has been

documented both for GERD and PUD (Howden et al., 1994;

Chiba et al., 1997; Selby et al., 2000; van Pinxteren et al.,

2003).


The groundwork for the current therapeutic approaches

to controlling gastric acid production was laid in the 19th

century. Through the work of many scientists (e.g., Prout,

Gunzberg, Beaumont, Heidenhain, and Cooper), the phys-

iology of gastric secretion and the pathophysiology of PUD

have been increasingly elucidated. There has also been an

increasing understanding of the role of gastric acid in

GERD. By the mid-20th century, this growing knowledge

led to several pharmaceutical companies (e.g., SmithKline

& French, Servier, Searle, and Astra) developing drugs to

inhibit the production of gastric acid.

4.1. H2 receptor antagonists and H3 receptor agonists

The development of H2RAs can be traced back to the

early 1960s when Sir James Black and his colleagues at

SmithKline & French embarked on a research program to

identify histamine receptors. This work resulted in the

development of burimamide, the first selective antagonist of

the H2 receptor. Burimamide was the lead compound in a

search for more potent antagonists. It was tested in humans

but was not sufficiently active by the oral route to be

developed as a medicine. Chemical modifications and

subsequent screening led to the development of cimetidine.

This H2RAwas approved in 1976 in the UK and in 1977 in

the USA and was the progenitor of a group of compounds

that has been recognized as a breakthrough in the treatment

of PUD and GERD.

H2RAs are more effective than antacids at providing

symptom relief and lesion healing in both PUD and GERD.

However, these compounds have a relatively short duration

of effect and their effects are mitigated by food ingestion. A

further limitation is that tolerance can develop after a few

days of continuous dosing, a clinically relevant phenom-

enon in some patients (Lachman & Howden, 2000;

Komazawa et al., 2003).

The work of Black and colleagues caused a resurgence of

interest in histamine, and a third histamine receptor, H3, has

since been discovered. This receptor is detected in the

peripheral and central nervous system and in several

nonneural tissues (Barocelli & Ballabeni, 2003). Centrally

located H3 receptors probably contribute to the regulation of

acid secretion and inhibit cholinergic-stimulated acid

production. The H3 receptor agonist R(a)-methylhistaminehas had variable and contradictory effects on gastric acid

secretion in vitro and in vivo (Barocelli & Ballabeni, 2003).

Thus, it is difficult to predict whether this or other agents

will be effective treatments for acid-related diseases.

Currently, there does not appear to be an H3 receptor

agonist in clinical development for the treatment of gastric

acid-related diseases.

4.2. Muscarinics and cholecystokinin2 receptor antagonists

Other stimulatory pathways in gastric acid secretion have

been the focus of approaches to block acid production; they

include muscarinic (M3) and cholecystokinin2 (CCK2,

gastrin) receptor antagonists. There are currently no M3-

specific antagonists available in the clinical setting for the

treatment of acid-related diseases. However, anticholinergic

agents (e.g., pirenzepine, telenzepine, and atropine) have a

long history in the treatment of PUD (Eltze et al., 1985;

Fiorucci et al., 1988), but as they inhibit M1 receptors at

locations outside the stomach, they are associated with

anticholinergic side effects that limit their use.

The development of the CCK2 antagonists has been

reviewed by Black and Kalindjian (2002). Acting via CCK2receptors, gastrin mediates acid secretion primarily by

causing release of histamine from enterochromaffin-like

(ECL) cells and also, at least in vitro, by directly stimulating

parietal cells (Kopin et al., 1992; Cabero et al., 1993; Prinz

et al., 1993, 1994). A number of CCK2 receptor antagonists

have been evaluated and shown to reduce acid secretion

(YF476 [Steel, 2002], YM022 [Nishida et al., 1994],

RP73870 [Pendley et al., 1995], spiroglumide [Beltinger

et al., 1999], and S0509 [Takeuchi et al., 1999]), but their

development has been discontinued.

Two CCK2 receptor antagonists in clinical studies

include Z360 and itriglumide (Vakil, 2004). Z360 is in

early clinical development for reflux esophagitis and gastric

ulcer. In preclinical studies, Z360 was more potent than

famotidine at inhibiting pentagastrin-stimulated acid secre-

tion and also reduced meal-induced acid production in rats

and dogs (Miura et al., 2001; Morita et al., 2001). The status

of itriglumide is uncertain: Phase I clinical studies on

gastrin- and meal-induced gastric secretion were reported to

be in progress, and Phase II clinical studies in peptic ulcer

were scheduled to be complete by the end of 2003

(Rottapharm, 2004). In pentagastrin-stimulated rats, itriglu-

mide was less potent than ranitidine or omeprazole when

administered intravenously, but intraduodenally, it was 3

times more potent than ranitidine and twice as potent as

omeprazole (Makovec et al., 1999).

It is unlikely that there will be a role for CCK2antagonists alone as alternative antisecretory therapy to

PPIs or H2RAs, especially given the development of

tolerance with at least 1 member of this class (i.e., YF476;

Black & Kalindjian, 2002; Steel, 2002).

4.3. Proton pump inhibitors

One of several companies that started up research

programs with the intention of developing a drug that

would reduce gastric acid secretion was Hässle (a

research unit within AB Astra, Sweden). The initial idea

was to find a drug to inhibit the release of gastrin but the

approach was not successful. However in 1971 the French

company Servier reported (Malen & Danree, 1971) that

the compound CMN 131 (a gastrin receptor antagonist)

inhibited acid secretion but resulted in acute toxicity in

animals. The thioamide group of this compound was

assumed to be responsible for its toxicity, and therefore

Fig. 1. Mode of action of a PPI. PPIs are weak bases that concentrate in the

parietal cell canaliculus, where they undergo a proton-catalyzed, 3-step

process to generate the active sulfenamide. This moiety interacts covalently

with sulfhydryl groups on cysteine residues in the transmembrane domains

of the gastric H+,K+-ATPase and thereby inhibits the enzyme.


this group was eliminated by incorporating it into or

between heterocyclic ring systems. Based on this strategy,

substituted benzimidazoles with potent antisecretory prop-

erties but without acute toxicity were identified. A

number of such compounds (H124/26, timoprazole, and

picoprazole) were selected as candidate drugs during the

1970s, but all were associated with safety problems in

long-term toxicity studies. The breakthrough came with

the synthesis of omeprazole in 1979. This compound was

the most potent of a series of candidate drugs synthesized

and tested, and it did not show any significant effects in

the initial repeat-dose toxicity studies in animals. Thus,

the project started with a lead compound CMN 131, a

gastrin receptor antagonist, and ended with the discovery

of a complete new mechanism of action: inhibition of

gastric H+,K+-ATPase.

Omeprazole was taken into clinical trials, and the first

publication on the efficacy in man was in 1983 (Gustavsson

et al., 1983). This and subsequent studies led to omeprazole

becoming available in Europe in 1988. Omeprazole is

recognized as a major breakthrough in the treatment of

GERD and PUD. Moreover, omeprazole is effective in the

treatment of Zollinger–Ellison syndrome (Lambers et al.,

1984), which was previously difficult to treat and often

required surgical intervention.

Other available PPIs include lansoprazole, pantoprazole,

rabeprazole, and esomeprazole, all of which are substituted

benzimadazoles. Tenatoprazole, which is in clinical devel-

opment, has an imidazopyridine ring instead of a benzima-

dazole ring but has the same mechanism of action as the

substituted benzimadazole PPIs. As illustrated by omepra-

zole, PPIs are more effective than H2RAs at reducing

intragastric pH and maintaining pH >4 for a longer period

of time (Bell et al., 1992). They are generally accepted to be

superior to H2RAs in the treatment of GERD and PUD, as

they relieve symptoms and heal lesions more effectively

than H2RAs (Chiba et al., 1997; van Pinxteren et al., 2001;

Salas et al., 2002). In addition, tolerance to PPIs has not

been documented (Tefera et al., 2001). The superior efficacy

of PPIs over H2RAs is attributed to the fact that they inhibit

gastric H+,K+-ATPase, independently of the nature of the

stimulus.

All PPIs are lipophilic compounds with weak base

properties and pKa values ranging from 3.8 to 5.0. Thus,

they easily penetrate cell membranes and are accumulated in

the highly acidic (pH ¨1.0) parietal cell canaliculi. For

example, omeprazole with a pKa of 4.0 would theoretically

concentrate 1000-fold in the parietal cell versus blood.

However, this equilibrium concentration will probably never

be achieved in vivo as the chemical stability of the

protonated form of omeprazole is extremely low. Within

milliseconds, the compound is degraded to form the active

inhibitor, the sulfenamide (Lindberg et al., 1987; Fig. 1).

Again, almost instantaneously, the sulfenamide binds

covalently to cysteine residues (in particular, cysteine 813

although other residues are involved) on the luminal side of

the a-subunit of the enzyme (Besancon et al., 1993, 1997).These cysteine residues do not appear to be necessary for

enzyme functioning, but their binding of the sulfenamide

may disrupt or prevent the conformational change of the

enzyme.

This mechanism of action results in the unique character-

istics of the pharmacokinetic–pharmacodynamic effect

pattern of PPIs. The inhibitory effect on acid secretion is

related to the amount of sulfenamide formed, which, for a

given dose, is related to the area under the plasma

concentration time curve (AUC). Thus, the maximal effect

of a given dose is correlated with the AUC rather than to the

Cmax, and there is no direct correlation between blood

plasma concentration and effect at any given time. The

duration of effect is determined by the half-life of the

sulfenamide–enzyme complex (at least 24 hr but may be as

long as 48 hr; Metz et al., 2002), rather than to the half-life

of the PPI in blood plasma (e.g., 1–2 hr for omeprazole).

Therapeutic oral doses of PPIs reach steady state and thus

achieve their maximal effect levels after 4–5 days of daily

dosing (Fig. 2). Therefore, PPIs in therapeutic doses have a

slow, cumulative onset of effect (e.g., 24–43% inhibition of

acid secretion on the first day of treatment and ¨80%

inhibition at steady state (Cederberg et al., 1992; Dammann

& Burkhardt, 1999).

After PPI administration, there is a return of acid

secretion that is partly due to de novo synthesis of the

enzyme (Im et al., 1985a; Gedda et al., 1995) and partly to

the dissolution of the enzyme–sulfenamide complex, owing

to the effect of endogenous glutathione (Im et al., 1985b;

Fujisaki et al., 1991). This dissociation may lead to the

reactivation of the enzyme, together with the release of a

sulfide corresponding to the PPI.

In addition to a cumulative onset of effect, PPIs have a

relatively slow onset of acute effect. PPIs are chemically

unstable at low pH, such as in the stomach (e.g., the half-

lives at pH 1.2 range from 1.3 to 4.7 min; Kromer et al.,

1998) and must be given in an acid-protected form, such as

enteric-coated granules. While such preparations allow PPIs

Fig. 2. Pharmacodynamic profile of a PPI demonstrating that there is a cumulative onset of effect at therapeutic oral doses.


to reach the intestine intact from where they can be

absorbed, they delay absorption.

Although PPIs have markedly advanced the treatment

of acid-related diseases, areas of medical need remain

(e.g., faster and more complete symptom relief, more

rapid healing). The degree and speed of onset of symptom

relief are important to patients (Kleinman et al., 2002).

However, not all patients with GERD experience complete

symptom relief after initial PPI therapy, which may

explain why many patients are unsatisfied with PPI

treatment (Crawley & Schmitt, 2000; Robinson & Shaw,

2002; Bytzer, 2003). Improved control of 24-hr intra-

gastric acidity would be likely to enhance symptom

resolution and healing, but as the limitations of PPIs

mainly relate to their shared mechanism of action, it is

likely that only incremental developments can be

achieved, making it attractive to consider other potential

approaches. The clinical utility of many of these strategies

(e.g., H3 receptor agonists, CCK2 receptor antagonists) is

likely to be limited, but 1 class of developmental agents

that holds promise for the treatment of acid-related

diseases is the P-CABs.

5. Potassium-competitive acid blockers

5.1. Development of the

potassium-competitive acid blocker class

During acid secretion, the surface of gastric

H+,K+-ATPase faces the extremely acidic parietal cell

canaliculus with a high affinity for K+. Given the

importance of the cation for enzyme function, agents that

compete with the binding of K+ have the potential to

block acid secretion. It is this principle that underlies the

mode of action of P-CABs (previously known as acid

pump antagonists or APAs). These agents can be classified

as imidazopyridines (e.g., SCH28080, AZD0865, and

BY841), pyrimidines (e.g., revaprazan), imidazonaphthyr-

idine (e.g., soraprazan), or quinolines (e.g., SK&F96067

and SK&F97574; Wallmark et al., 1987; Keeling et al.,

1991; Wurst & Hartmann, 1996; Tsukimi et al., 2000;

Park et al., 2003b; Briving et al., 2004).

The prototype P-CAB, SCH28080, was developed by

Schering-Plough (Ene et al., 1982; Long et al., 1983). In a

study published in 1982, this compound was shown to

inhibit gastric acid secretion in humans (Ene et al., 1982),

although its mechanism of action was not fully known at the

time. Subsequently, SCH28080 was shown to block gastric

H+,K+-ATPase by competing with K+ (Beil et al., 1986).

The development of SCH28080 ceased because of hepatic

toxicity. Despite this, the SCH28080 molecule has been

used extensively to investigate the functions of gastric

H+,K+-ATPase and provide insights into the mechanism of

action of the P-CAB class. Other compounds based on

SCH28080 were found to have improved bioavailability and

safety profiles (Kaminski et al., 1987, 1989; Scott et al.,

1987), including SCH33405. This compound was also

tested in humans (Sachs et al., 1995), but no publications

on these clinical studies are available.

Other P-CABs have provided further proof of principle

for this class of agents. SK&F96067 (BY067; Keeling et al.,

1988, 1991) was one of a series of quinolones that inhibited

gastric acid secretion and was investigated in early clinical

studies. It inhibited pentagastrin-simulated acid secretion

and was more effective than ranitidine in raising intragastric

pH (Pope & Parsons, 1993). SK&F97574 (BY574), an

analogue of SK&F96067 but with a longer duration of

action, inhibited H+,K+-ATPase in a potassium-competitive

fashion, blocked H+ transport in isolated gastric vesicles

(Pope et al., 1995), and inhibited histamine-stimulated

gastric acid secretion in the Heidenhain pouch dog (Parsons

et al., 1995). Preliminary toxicological studies did not reveal

any untoward findings (Leach et al., 1995), but although

taken into clinical studies (Pope & Parsons, 1993), the drug

is no longer under development. BY841 was found to be

more potent and more selective for the H+,K+-ATPase than

both SK&F96067 and SK&F97574 (Wurst & Hartmann,

1996). Based on positive preclinical and clinical Phase I

data (Wurst & Hartmann, 1996), BY841 entered Phase II

studies (e.g., comparing healing of reflux esophagitis

following BY841 and omeprazole treatment), but its

development was subsequently discontinued without pub-

lication of trial results.

Four representatives of the P-CAB class are currently in

clinical development to improve the treatment of acid-

Fig. 3. Mode of action of a P-CAB. As a P-CAB concentrates in the parietal

cell canaliculi, it is instantaneously protonated. It then binds ionically to the

gastric H+,K+-ATPase and inhibits acid secretion.


related diseases (Table 1), with most information being

available on AZD0865 and revaprazan. Papers have been

published recently on other molecules (e.g., SPI447 [Ushiro

et al., 1997; Tsukimi et al., 2000], YJA20379-8 [Sohn et al.,

1999; Kim et al., 2000], and YJA20379-6 [Kim et al.,

1998]), but it is not clear if these agents are being evaluated

in humans.

5.2. Mechanism of potassium-competitive

acid blocker inhibition of gastric H+,K+-ATPase

P-CABs are lipophilic, weak bases that have high pKavalues and are stable at low pH. This combination of

properties allows them to concentrate in acidic environ-

ments. For example, the concentration of a P-CAB with a

pKa of 6.0 would theoretically be expected to be 100,000-

fold higher in the parietal cell canaliculus (pH 1) than in the

plasma (pH 7.4). The concentration of P-CABs in the gastric

mucosa is demonstrated by in vitro and in vivo studies with

AZD0865 and revaprazan (Park et al., 2003a; Briving et al.,

2004; Holstein et al., 2004c). In a radiolabeling study in rats,

the concentration of revaprazan reached peak levels in most

tissues at 4 hr after oral dosing. At 8 hr after oral dosing, the

radioactivity was highly localized in the gastric wall (Park et

al., 2003a). AZD0865 was tested in 2 different preparations

with isolated H+,K+-ATPase: in ion-tight and in ion-leaky

vesicles. In the ion-tight vesicle preparation, the high-

affinity K+-binding site faces intravesically and the vesicles

have an acidic internal environment. In the ion-leaky

vesicle, no acidic environment is formed. AZD0865 was

found to be more potent in ion-tight versus ion-leaky

vesicles, which suggests that it concentrates in regions of

low pH (Briving et al., 2004). Further evidence that

AZD0865 concentrates in acidic environments is provided

by studies in Heidenhain pouch dogs. For example, the

concentration of AZD0865 in gastric juice exceeded the

plasma concentration at ¨2 hr after dose (Holstein et al.,

2004b), and while the P-CAB was detectable in gastric juice

at 24 hr postdose, it was undetectable in plasma in most

animals (Holstein et al., 2004c).

On entering an acidic environment, P-CABs are instantly

protonated and it is in this form that it is thought to bind to

and inhibit the enzyme (Fig. 3). In keeping with this

hypothesis, the potency of P-CABs increases as pH falls

Table 1

P-CABS currently in clinical development

P-CAB Description Clinical

development

phase

Company

AZD0865 Imidazopyridine Phase II AstraZeneca

CS526 (R105266) Pyrrolopyridazine Phase I Sankyo and

Ube/Novartis

Revaprazan

(YH1885, Revanex)

Pyrimidine Phase III Yuhan

Soraprazan (BY359) Imidazonaphthyridine Phase II Altana

(Briving et al., 1988, 2004; Keeling et al., 1991; Pope et al.,

1995; Tsukimi et al., 2000). In ion-leaky vesicles, the IC50value for AZD0865 at pH 6.4 was ¨7 times lower

compared with the value at pH 7.4 (0.13 and 1.00 AM,respectively). This corresponds very well to the availability

of 6- to 7-fold more protonated drug at pH 6.4 (Briving et

al., 2004) The protonated form of a P-CAB inhibits the

H+,K+,-ATPase by binding ionically to it (Wallmark et al.,

1987; Keeling et al., 1991; Tsukimi et al., 2000; Park et al.,

2003b; Briving et al., 2004), as illustrated by the recovery of

enzyme activity after washout of AZD0865 and revaprazan

(Park et al., 2003a; Briving et al., 2004).

There appear to be separate binding sites on the gastric

H+,K+-ATPase for P-CABs and K+. For example, K+

affinity is not affected by mutations in the membrane

domains that reduce affinity for SCH28080 (and vice versa;

Asano et al., 1999; Lambrecht et al., 2000; Munson et al.,

2000; Vagin et al., 2001, 2002). Nevertheless, the K+-

competitive nature of P-CAB binding indicates that some of

the residues at or near the cation binding sites are involved

in P-CAB binding. Research indicates that P-CABs have a

luminal site of action (Wallmark et al., 1987; Keeling et al.,

1989; Pope & Parsons, 1993; Briving et al., 2004).

Investigations with SCH28080 indicate the likely binding

site of P-CABs. An early photoaffinity labeling study

suggested that the first extracellular loop (between M1

and M2) was the direct binding site of SCH28080 (Munson

et al., 1991), although subsequent mutational studies

indicate that this is not the case (Asano et al., 1997,

1999). Several areas of research (e.g., mutational studies,

NMR studies) indicate that the SCH28080 binding site is

located in the M1 to M6 and possibly M8 domains (Watts et

al., 2001; Vagin et al., 2002, 2003; Asano et al., 2004; Yan

et al., 2004). SCH28080 and SPI447 both bind in a cavity

formed by the M1, M4, M5, M6, and M8 transmembrane

segments, and by loops formed by M5/M6, M7/M8, and

M9/M10 (Asano et al., 2004). This cavity appears to be

separate from the cation-binding site.

P-CABs are believed to bind to gastric H+,K+-ATPase

when the enzyme is in its phosphorylated E2 form and/or

in its (nonphosphorylated) E2 form (Keeling et al., 1989;

Mendlein & Sachs, 1990). Support is provided by the

observed 10-fold increase in the binding affinity of

SCH28080 for the enzyme in the presence of ATP


(Wallmark et al., 1987; Keeling et al., 1989). Conceptually,

the binding of a P-CAB to the phosphorylated E2 form is

consistent with the fact that K+ binds to the same form of

the enzyme and that P-CABs compete with this ion. The

docking of a P-CAB in its binding site on the gastric

H+,K+-ATPase appears to stabilize the enzyme in the E2conformation (Asano et al., 2004) and prevents the

translocation of H+ ions. A P-CAB molecule may be

unable to bind to the E1 form of the enzyme due to re-

arrangement of transmembrane segments and loops that

form the P-CAB binding site. It appears that the

orientation of the loop between the M3 and M4 domains

in the E1 form of the enzyme prevents a P-CAB molecule

from occupying its binding site (Asano et al., 2004).

5.3. Selectivity of potassium-competitive

acid blockers for gastric H+,K+-ATPase

There are 3 main classes of enzymes that translocate

H+ in biological systems: P-type, F-type, and V-type of

H+-ATPases. V-type H+-ATPases are found in endomem-

branes and plasma membranes, and the F-type is located

in mitochondria. The P-type H+-ATPases are part of a

general class of ion-translocating ATPase that are charac-

terized by the formation of a covalently phosphorylated

enzyme intermediate as part of their catalytic cycle

(Rabon & Reuben, 1990). Members of this class include

gastric H+,K+-ATPase, Na+,K+-ATPase, and Ca+-ATPases

of sarcoplasmic reticulum and plasma membrane

(Sachs, 1994). The amino acid sequence of the human

H+,K+-ATPase is highly homologous (¨60%) to that of

the human Na+,K+-ATPase (Maeda et al., 1990). The

importance of K+ for physiological functioning dictates

that P-CABs must not affect other processes which

involve this cation, such as the ion exchange by

Na+,K+-ATPase. Data from studies of P-CABs no

longer in development show that they have a much

higher selectivity for gastric H+,K+-ATPase than for

Na+,K+-ATPase (Keeling et al., 1991; Kromer et al., 2000;

Tsukimi et al., 2000): SCH28080 has little effect on

Na+,K+-ATPase activity even at a concentration of 100

AM compared with an IC50 value of 1.3 AM for theinhibition of the H+,K+-ATPase (Beil et al., 1986);

SK&F96067 was 32-fold more selective for H+,K+-ATPase

than Na+,K+-ATPase; and SK&F97574 was 60-fold more

selective for H+,K+-ATPase than Na+,K+-ATPase (Pope et

al., 1995). The data available on compounds that are

currently in clinical development also demonstrate high

selectivity for gastric H+,K+-ATPase. AZD0865 is more

than 100-fold selective for gastric H+,K+-ATPase over

Na+,K+-ATPase. At a concentration of 100 AM, itreduced Na+,K+-ATPase activity by only 9% compared

with an IC50 value of 1.0 AM for the inhibition of theH+,K+-ATPase (Andersson et al., 2004). Revaprazan is

also more than 100-fold more selective for H+,K+-ATPase

over Na+,K+-ATPase (Park et al., 2003b).

H+,K+-ATPase isoforms found in rat and guinea pig

distal colon are not inhibited significantly by SCH28080

(Cougnon et al., 1996). In support of the targeting of

P-CABs for gastric H+,K+-ATPase in the parietal cell

canaliculus, AZD0865 does not appear to affect kidney

function despite the occurrence of the enzyme in the

cortical collecting duct of the kidney (Andersson et al., in

press). The weak base properties and, thus, the super-

concentration of P-CABs at areas of low pH probably

contribute significantly to the targeting, as P-CABs are

unlikely to concentrate to any great extent at sites with

relatively high pH.

P-CABs are also more selective for gastric H+,K+-ATPase

than for other H+-translocating ATPases, such as

vacuolar-ATPases, that are responsible for generating an

acidic pH in intracellular compartments. This selectivity

is illustrated by the selectivity of SK&F 96067 for

vacuolar-ATPase derived from avian osteoclasts and by the

insensitivity to SCH28080 in a similar preparation (Pope

& Sachs, 1992; Mattsson et al., 1993). As this type of

ATPase is highly conserved, it is unlikely that mammalian

vacuolar-ATPase will be inhibited by P-CABs.

5.4. Pharmacokinetics of

potassium-competitive acid blockers

After oral doses, P-CABs rapidly achieve peak plasma

concentrations in both animals and humans. This is partly

because the compounds are stable at low pH and so can be

administered as immediate-release formulations. A clinical

study of BY841 reported peak serum concentrations

between 0.5 and 1.5 hr after administration (Wurst &

Hartmann, 1996). In a volunteer study, the plasma concen-

tration of revaprazan reached peak levels within 1.3 to 2.5 hr

after a single dose (Yu et al., 2004). The Cmax of AZD0865

after oral administration to Heidenhain pouch dogs was

generally achieved 0.5–1 hr postdose (Andersson et al.,

2004). In humans, AZD0865 was rapidly absorbed and

maximum plasma concentrations occurred within 1 hr in

most subjects (Nilsson et al., 2005).

The P-CABs investigated to date exhibit linear pharma-

cokinetics. The Cmax and AUC of BY841 increased in

proportion with increasing dose (20–400 mg; Wurst &

Hartmann, 1996). The serum t1/2 of BY841 was unchanged

on repeated dosing, although a slight increase in AUC was

observed (Wurst & Hartmann, 1996). The oral bioavail-

ability of AZD0865 in Heidenhain pouch dogs was ¨50%

and the compound had linear pharmacokinetics over the

dose range 0.125–1 Amol/kg (Holstein et al., 2004b,2004d). Consistent with the findings from animal studies,

there was a proportional increase in AUC and Cmax with

dose in human subjects receiving single oral doses of

AZD0865 (0.08–4.0 mg/kg; Nilsson et al., 2005). The

plasma concentration–time profiles of AZD0865 are inde-

pendent of the number of doses given (Holstein et al.,

2004b, 2004d). For example, there was no increase in the


plasma concentration of AZD0865 as a result of repeated

administration to chronic fistula rats or Heidenhain pouch

dogs (Holstein et al., 2004a, 2004c).

In rats and dogs, revaprazan had linear pharmacoki-

netics for oral doses of 2–30 mg/kg. In this dose range,

oral bioavailability was 41–47% in rats and 43–59% in

dogs (Park et al., 2003a). However, at doses above

200 mg/kg, the AUC of revaprazan did not show dose

proportionality, which was attributed to poor water

solubility of the drug (Han et al., 1998). On repeated

administration to rats and dogs, the daily pharmacokinetic

profiles of revaprazan were similar during 7 days of

dosing (Park et al., 2003a). A clinical study confirmed

that revaprazan has linear pharmacokinetic characteristics

and demonstrated little accumulation after multiple admin-

istrations (Yu et al., 2004).

The lipophilicity and chemical stability of the P-CAB,

together with the ionic binding between the agent and the

H+,K+-ATPase, facilitates an equilibrium between blood and

the secretory canaliculi, albeit with the concentration in the

latter being much higher.

5.5. Pharmacodynamics of

potassium-competitive acid blockers

The rapid absorption of P-CABs is mirrored by a fast

onset of acid inhibition. In animal and clinical studies,

there was a rapid inhibition of acid secretion with BY841

(Wurst & Hartmann, 1996; Kromer et al., 2000). A single

dose of BY841 quickly raised intragastric pH to ¨6 in

the pentagastrin-stimulated fistula dog and did so faster

than omeprazole (Wurst & Hartmann, 1996). In healthy

volunteers, a single 50 mg oral dose of BY841 increased

intragastric pH to about 6 within 30–60 min (Wurst &

Hartmann, 1996). For AZD0865, peak antisecretory effect

in the rat was achieved within 2 hr after an oral dose of

1 Amol/kg (Holstein et al., 2004d). The onset of effectwas also fast in dogs (e.g., peak antisecretory effect was

achieved within 3 hr postdose; Holstein et al., 2004d). In

humans, high doses of AZD0865 resulted in over 95%

inhibition of acid secretion within 1 hr after oral dosing

(Nilsson et al., 2005). In humans, revaprazan at single

doses of 150 mg and above rapidly increased mean

intragastric pH (Yu et al., 2004).

Fig. 4. Theoretical pharmacodynamic profile of a P-CAB demonstrating that these

of acid inhibition with subsequent, repeated doses.

The peak levels of acid secretion inhibition with

AZD0865 did not change over 5- and 14-day dosing

periods in Heidenhain pouch dogs and full effect was

achieved with the first dose (Andersson et al., 2004; Hol-

stein et al., 2004b). Similarly, intragastric pH was similar at

days 1 and 7 in a clinical study of revaprazan (Park et al.,

2002; Fig. 4).

P-CABs exhibit a classical (sigmoid) dose–response

profile, with the magnitude and duration of effect being

determined by dose, pKa, and plasma half-life. BY841 had a

dose-dependent duration of action in animal studies

(Kromer et al., 2000). In chronic fistula rats, AZD0865

provided dose-dependent inhibition of acid secretion (ED50value for inhibition of acid output of 0.3 Amol/kg), withdoses above 10 Amol/kg almost completely inhibitinggastric acid production 24 hr after administration (Holstein

et al., 2004a). Dose-dependent effects were also seen in

Heidenhain pouch dogs (ED50=0.28 Amol/kg; Holstein etal., 2004b). Confirming the relationship between pharma-

cokinetics and effect, there was a close correlation between

maximum inhibition of acid output and the logarithm of

Cmax for AZD0865 (EC50=130 nmol/L; Andersson et al.,

2004). In humans, AZD0865 demonstrated a dose–effect

relationship with a dose-dependent duration of inhibition of

acid secretion; more than 95% inhibition was sustained for

up to 15 hr for 0.8 and 1 mg/kg doses (EC50=100 nmol/L;

Nilsson et al., 2005). Dose-related pharmacodynamics were

noted in 46 healthy volunteers after single doses of

revaprazan (Yu et al., 2004). In a multiple-dose, crossover

study in which patients received 100, 150, and 200 mg once

daily for 7 days, mean intragastric pH on day 7 was 1.9, 3.5,

and 4.2, respectively (Park et al., 2002).

5.6. Pharmacodynamic comparisons of

potassium-competitive acid blockers with other agents

To date, there have been only a limited number of

published studies comparing P-CABs and other inhibitors of

acid secretion. In the pentagastrin-stimulated fistula dog, a

single dose of BY841 raised intragastric pH more rapidly

than omeprazole or ranitidine and elevated it almost to

neutrality, whereas omeprazole and ranitidine produced only

a moderate increase in pH (Kromer et al., 2000). When

histamine was used as a stimulus in the Ghosh-Schild rat,

agents achieve their full effect with the first dose and provide similar levels

Fig. 5. Comparison of acid blockade by the P-CAB, BY841, and omeprazole, a PPI. Note acid inhibition occurring within 30 min and the higher pH with

BY841. Reproduced from Wurst and Hartmann (1996) with permission from Yale J Biol Med.


BY841 and ranitidine displayed similar efficacy (Kromer et

al., 2000). Revaprazan was 3 times more potent than

omeprazole at inhibiting basal acid secretion in pylorus-

ligated rats and chronic fistula rats (Park et al., 2003b), and

was also more potent than omeprazole in inhibiting

histamine-stimulated gastric acid secretion in Heidenhain

pouch dogs. However, there was no significant difference in

inhibitory potency between revaprazan and omeprazole on

pentagastrin-stimulated gastric acid secretion in the lumen-

perfused rat (Park et al., 2003b). Soraprazan was found to be

more effective than ranitidine in raising pH within the

mucous layer of the fistula dog (Kromer et al., 2000).

There is only 1 published study in humans that allows

direct comparison to be made between P-CABs and other

therapies, but it does indicate pharmacodynamic differences

between the compounds. BY841 100 mg twice daily

markedly elevated intragastric pH and prolonged the

percentage of time at which pH was �4 on the first day ofdosing (Wurst & Hartmann, 1996; Fig. 5). In contrast,

omeprazole 20 mg once daily had only minor effects. After 7

days of dosing, BY841 was judged to be at least comparable

to omeprazole. The authors of the study expected the

differences between the agents to translate into a shortening

of healing time and a more rapid relief of symptoms. Taken

together, this clinical study and the animal studies indicate

that P-CABs offer more rapid and more profound elevation

of pH than a PPI or an H2RA, although the relative effects

appear to differ according to the model employed.

6. Summary

The evolution of our understanding of the biochemistry

and physiology of gastric acid secretion has led to the

development of therapies to inhibit gastric acid secretion.

PPIs are currently recognized to be the most effective

available agents for the treatment of acid-related diseases.

They offer superior symptom control and healing rates

compared with H2RAs in both PUD and GERD. However,

PPIs exhibit a delayed onset of acute effect and achieve full

effect only slowly and incrementally over several dose cycles.

A number of alternative therapeutic strategies have been

pursued with the objective of further improving the manage-

ment of acid-related diseases. Of these, the agents that have

progressed the furthest are CCK2 receptor antagonists and

P-CABs, with representatives of both classes in clinical trials.

CCK2 receptor antagonists are unlikely to become

alternative therapies to H2RAs or PPIs, especially given the

phenomenon of tolerance observed with an example of the

class. Thus, P-CABs appear to offer the most promise of the

newer agents, with initial studies comparing P-CABs with

PPIs suggesting pharmacodynamic differences between the 2

classes. P-CABs rapidly achieve therapeutic plasma levels

and concentrate in the acidic environment of the parietal cell

canaliculus. Once there, these compounds block gastric

H+,K+-ATPase by a K+ competitive binding at or near the

K+ binding site. They achieve their full effect quickly and

provide similar acid inhibition with the first dose and

subsequent, repeated doses. The results of comparative

clinical studies with PPIs will help to define the place of P-

CABs in the management of acid-related diseases.

References

Andersson, K., Aurell Holmberg, A., Briving, C., & Holstein, B. (2004).

Preclinical profile of AZD0865, a novel, selective, potassium-compet-

itive acid blocker. Gastroenterology 126, A-56.

Andersson, K., Hallberg, H., & Holstein, B. (in press). AZD0865, a

potassium-competitive acid blocker (P-CAB), does not affect kidney

gastric H+,K+-ATPase in the rat. Gut.


Asano, S., Matsuda, S., Tega, Y., Shimizu, K., Sakamoto, S., & Takeguchi,

N. (1997). Mutational analysis of putative SCH 28080 binding sites of

the gastric H+, K+-ATPase. J Biol Chem 272, 17668–17674.

Asano, S., Matsuda, S., Hoshina, S., Sakamoto, S., & Takeguchi, N. (1999).

A chimeric gastric H+,K+-ATPase inhibitable with both ouabain and

SCH 28080. J Biol Chem 274, 6848–6854.

Asano, S., Yoshida, A., Yashiro, H., Kobayashi, Y., Morisato, A., & Ogawa,

H., et al. (2004). The cavity structure for docking the K(+)-competitive

inhibitors in the gastric proton pump. J Biol Chem 279, 13968–13975.

Barocelli, E., & Ballabeni, V. (2003). Histamine in the control of gastric

acid secretion: a topic review. Pharmacol Res 47, 299–304.

Beil, W., Hackbarth, I., & Sewing, K. F. (1986). Mechanism of gastric

antisecretory effect of SCH 28080. Br J Pharmacol 88, 19–23.

Beisvag, V., Falck, G., Loennechen, J. P., Qvigstad, G., Jynge, P.,

Skomedal, T., et al. (2003). Identification and regulation of the gastric

H+/K+-ATPase in the rat heart. Acta Physiol Scand 179, 251–262.

Bell, N. J., Burget, D., Howden, C. W., Wilkinson, J., & Hunt, R. H. (1992).

Appropriate acid suppression for the management of gastro-oesopha-

geal reflux disease. Digestion 51(Suppl 1), 59–67.

Beltinger, J., Hildebrand, P., Drewe, J., Christ, A., Hlobil, K., Ritz, M., et al.

(1999). Effects of spiroglumide, a gastrin receptor antagonist, on acid

secretion in humans. Eur J Clin Invest 29, 153–159.

Besancon, M., Shin, J. M., Mercier, F., Munson, K., Miller, M., Hersey,

S., et al. (1993). Membrane topology and omeprazole labeling of

the gastric H+, K(+)-adenosinetriphosphatase. Biochemistry 32,

2345–2355.

Besancon, M., Simon, A., Sachs, G., & Shin, J. M. (1997). Sites of reaction

of the gastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol

Chem 272, 22438–22446.

Black, J., & Kalindjian, S. (2002). Gastrin agonists and antagonists.

Pharmacol Toxicol 91, 275–281.

Briving, C., Andersson, B. M., Nordberg, P., & Wallmark, B. (1988).

Inhibition of gastric H+/K+-ATPase by substituted imidazo[1,2-a]pyr-

idines. Biochim Biophys Acta 946, 185–192.

Briving, C., Svensson, K., Maxvall, I., & Andersson, K. (2004). Mechanism

of action of AZD0865, an H+,K+-ATPase selective, potassium-

competitive acid blocker. Gastroenterology 126, A-333 (M1436).

Bytzer, P. (2003). Goals of therapy and guidelines for treatment success in

symptomatic gastroesophageal reflux disease patients. Am J Gastro-

enterol 98, S31–S39.

Cabero, J. L., Li, Z. Q., & Mardh, S. (1993). Gastrin action on aminopyrine

accumulation in isolated pig parietal cells requires cAMP. Biochim

Biophys Acta 1177, 245–252.

Cederberg, C., Lind, T., Rohss, K., & Olbe, L. (1992). Comparison of once-

daily intravenous and oral omeprazole on pentagastrin-stimulated acid

secretion in duodenal ulcer patients. Digestion 53, 171–178.

Chiba, N., De Gara, C. J., Wilkinson, J. M., & Hunt, R. H. (1997). Speed of

healing and symptom relief in grade II to IV gastroesophageal reflux

disease: a meta-analysis. Gastroenterology 112, 1798–1810.

Cougnon, M., Planelles, G., Crowson, M. S., Shull, G. E., Rossier, B. C., &

Jaisser, F. (1996). The rat distal colon P-ATPase alpha subunit encodes a

ouabain-sensitive H+, K+-ATPase. J Biol Chem 271, 7277–7280.

Crawley, J. A., & Schmitt, C. M. (2000). How satisfied are chronic

heartburn suffers with their prescription medications? Results of the

Patient Unmet Needs Survey. J Clin Outcomes Manag 7, 29–34.

Dammann, H. G., & Burkhardt, F. (1999). Pantoprazole versus omeprazole:

influence on meal-stimulated gastric acid secretion. Eur J Gastroenterol

Hepatol 11, 1277–1282.

Dedek, K., & Waldegger, S. (2001). Colocalization of KCNQ1/KCNE

channel subunits in the mouse gastrointestinal tract. Pflugers Arch 442,

896–902.

Duman, J. G., Pathak, N. J., Ladinsky, M. S., McDonald, K. L., & Forte, J.

G. (2002). Three-dimensional reconstruction of cytoplasmic membrane

networks in parietal cells. J Cell Sci 115, 1251–1258.

Dunbar, L. A., & Caplan, M. J. (2001). Ion pumps in polarized cells: sorting

and regulation of the Na+, K+- and H+, K+-ATPases. J Biol Chem 276,

29617–29620.

Eltze, M., Gonne, S., Riedel, R., Schlotke, B., Schudt, C., & Simon, W. A.

(1985). Pharmacological evidence for selective inhibition of gastric acid

secretion by telenzepine, a new antimuscarinic drug. Eur J Pharmacol

112, 211–224.

Ene, M. D., Khan-Daneshmend, T., & Roberts, C. J. (1982). A study of the

inhibitory effects of SCH 28080 on gastric secretion in man. Br J

Pharmacol 76, 389–391.

Fiorucci, S., Clausi, G. G., Farinelli, M., Santucci, L., Farroni, F., Pelli,

M. A., et al. (1988). Do anticholinergics interact with histamine H2

receptor antagonists on night intragastric acidity in active duodenal

ulcer patients? Am J Gastroenterol 83, 1371–1375.

Fiorucci, S., Santucci, L., Chiucchiu, S., & Morelli, A. (1992). Gastric

acidity and gastroesophageal reflux patterns in patients with esoph-

agitis. Gastroenterology 103, 855–861.

Forte, J. G., & Yao, X. (1996). The membrane-recruitment-and-recycling

hypothesis of gastric HCl secretion. Trends Cell Biol 6, 45–48.

Fujisaki, H., Shibata, H., Oketani, K., Murakami, M., Fujimoto, M., &

Wakabayashi, T., et al. (1991). Inhibitions of acid secretion by E3810

and omeprazole, and their reversal by glutathione. Biochem Pharmacol

42, 321–328.

Fujita, A., Horio, Y., Higashi, K., Mouri, T., Hata, F., Takeguchi, N., et al.

(2002). Specific localization of an inwardly rectifying K(+) channel,

Kir4.1, at the apical membrane of rat gastric parietal cells; its possible

involvement in K(+) recycling for the H(+)-K(+)-pump. J Physiol 540,

85–92.

Futai, M., Oka, T., Sun-Wada, G., Moriyama, Y., Kanazawa, H., & Wada,

Y. (2000). Luminal acidification of diverse organelles by V-ATPase in

animal cells. J Exp Biol 203(Pt 1), 107–116.

Gatto, C., Lutsenko, S., Shin, J. M., Sachs, G., & Kaplan, J. H. (1999).

Stabilization of the H,K-ATPase M5M6 membrane hairpin by K+ ions.

Mechanistic significance for p2-type ATPases. J Biol Chem 274,

13737–13740.

Gedda, K., Scott, D., Besancon, M., Lorentzon, P., & Sachs, G. (1995).

Turnover of the gastric H+,K(+)-adenosine triphosphatase alpha subunit

and its effect on inhibition of rat gastric acid secretion. Gastro-

enterology 109, 1134–1141.

Grahammer, F., Herling, A. W., Lang, H. J., Schmitt-Graff, A., Wittekindt,

O. H., Nitschke, R., et al. (2001). The cardiac K+ channel KCNQ1 is

essential for gastric acid secretion. Gastroenterology 120, 1363–1371.

Grove, O., Bekker, C., Jeppe-Hansen, M. G., Karstoft, E., Sanchez, G.,

Axelsson, C. K., et al. (1985). Ranitidine and high-dose antacid in

reflux oesophagitis. A randomized, placebo-controlled trial. Scand J

Gastroenterol 20, 457–461.

Gustavsson, S., Adami, H. O., Loof, L., Nyberg, A., & Nyren, O. (1983).

Rapid healing of duodenal ulcers with omeprazole: double-blind dose-

comparative trial. Lancet 2, 124–125.

Han, K. S., Kim, Y. G., Yoo, J. K., Lee, J. W., & Lee, M. G. (1998).

Pharmacokinetics of a new reversible proton pump inhibitor, YH1885,

after intravenous and oral administrations to rats and dogs: hepatic first-

pass effect in rats. Biopharm Drug Dispos 19, 493–500.

Hermsen, H. P., Koenderink, J. B., Swarts, H. G., & de Pont, J. J. (2000).

The carbonyl group of glutamic acid-795 is essential for gastric H+, K+-

ATPase activity. Biochemistry 39, 1330–1337.

Holstein, B., Florentzson, M., Andersson, M., & Andersson, K. (2004a).

AZD0865, a potassium-competitive acid blocker (P-CAB), has a long

duration of effect in the rat. Am J Gastroenterol 99(Suppl 10), S8.

Holstein, B., Holmberg, A., Florentzson, M., Aurell Holmberg, A.,

Andersson, M., & Andersson, K. (2004b). AZD0865, a potassium-

competitive acid blocker (P-CAB), provides predictable inhibition of

acid secretion with repeated dosing in the dog. Eur J Pharm Sci

23(Suppl 1), S8.


Andersson, M., & Andersson, K. (2004c). AZD0865–a new potas-

sium-competitive acid blocker–exhibits maximal gastric antisecretory

effects from first dose. Gastroenterology 126, A-334 (M1437).


Andersson, M., & Andersson, K. (2004d). Pharmacokinetic and


pharmacodynamic profiles of AZD0865, a novel, potassium-compet-

itive acid blocker. Gastroenterology 126, A-334 (M1440).

Howden, C. W., Burget, D. W., & Hunt, R. H. (1994). Appropriate acid

suppression for optimal healing of duodenal ulcer and gastro-oesopha-

geal reflux disease. Scand J Gastroenterol Suppl 201, 79–82.

Im, W. B., Blakeman, D. P., & Davis, J. P. (1985a). Irreversible inactivation

of rat gastric (H+-K+)-ATPase in vivo by omeprazole. Biochem Biophys

Res Commun 126, 78–82.

Im, W. B., Blakeman, D. P., & Sachs, G. (1985b). Reversal of antisecretory

activity of omeprazole by sulfhydryl compounds in isolated rabbit

gastric glands. Biochim Biophys Acta 845, 54–59.

Kaminski, J. J., Perkins, D. G., Frantz, J. D., Solomon, D. M., Elliott, A. J.,

Chiu, P. J., et al. (1987). Antiulcer agents: 3. Structure–activity–

toxicity relationships of substituted imidazo[1,2-a]pyridines and a

related imidazo[1,2-a]pyrazine. J Med Chem 30, 2047–2051.

Kaminski, J. J., Puchalski, C., Solomon, D. M., Rizvi, R. K., Conn, D. J.,

Elliott, A. J., et al. (1989). Antiulcer agents: 4. Conformational

considerations and the antiulcer activity of substituted imidazo[1,2-

a]pyridines and related analogues. J Med Chem 32, 1686–1700.

Keeling, D. J., Laing, S. M., & Senn-Bilfinger, J. (1988). SCH 28080 is a

lumenally acting, K+-site inhibitor of the gastric (H++K+)-ATPase.

Biochem Pharmacol 37, 2231–2236.

Keeling, D. J., Taylor, A. G., & Schudt, C. (1989). The binding of a K+

competitive ligand, 2-methyl,8-(phenylmethoxy)imidazo(1,2-a)pyridine

3-acetonitrile, to the gastric (H++K+)-ATPase. J Biol Chem 264,

5545–5551.

Keeling, D. J., Malcolm, R. C., Laing, S. M., Ife, R. J., & Leach, C. A.

(1991). SK&F 96067 is a reversible, lumenally acting inhibitor of the

gastric (H++K+)-ATPase. Biochem Pharmacol 42, 123–130.

Kim, K. B., Chang, M. S., Chung, Y. K., Sohn, S. K., Kim, S. G., & Choi,

W. S. (1998). Biochemical and pharmacological characteristics of 3-

butyryl-8-methoxy-4-[(2-thiophenyl)amino]quinoline, a new proton-

pump inhibitor, in rabbit gastric microsomes and in rats. J Pharm


Kim, H. J., Han, K. S., Kim, Y. G., Chung, Y. K., Chang, M. S., & Lee, M.

G. (2000). Pharmacokinetics of a new proton pump inhibitor, YJA-

20379-8, after intravenous and oral administration to spontaneously

hypertensive rats and DOCA-salt-induced hypertensive rats. Biopharm

Drug Dispos 21, 293–302.

Kleinman, L., McIntosh, E., Ryan, M., Schmier, J., Crawley, J.,

Locke, G. R., et al. (2002). Willingness to pay for complete

symptom relief of gastroesophageal reflux disease. Arch Intern Med

162, 1361–1366.

Koenderink, J. B., Swarts, H. G., Willems, P. H., Krieger, E., & de Pont, J.

J. (2004). A conformation-specific interhelical salt bridge in the K+

binding site of gastric H,K-ATPase. J Biol Chem 279, 16417–16424.

Komazawa, Y., Adachi, K., Mihara, T., Ono, M., Kawamura, A., Fujishiro,

H., et al. (2003). Tolerance to famotidine and ranitidine treatment after

14 days of administration in healthy subjects without Helicobacter

pylori infection. J Gastroenterol Hepatol 18, 678–682.

Kopin, A. S., Lee, Y. M., McBride, E. W., Miller, L. J., Lu, M., Lin, H. Y.,

et al. (1992). Expression cloning and characterization of the canine

parietal cell gastrin receptor. Proc Natl Acad Sci U S A 89, 3605–3609.

Kraut, J. A., Helander, K. G., Helander, H. F., Iroezi, N. D., Marcus, E.

A., & Sachs, G. (2001). Detection and localization of H+-K+-

ATPase isoforms in human kidney. Am J Physiol Renal Physiol 281,

F763–F768.

Kromer, W., Kruger, U., Huber, R., Hartmann, M., & Steinijans, V. W.

(1998). Differences in pH-dependent activation rates of substituted

benzimidazoles and biological in vitro correlates. Pharmacology 56,

57–70.

Kromer, W., Postius, S., & Riedel, R. (2000). Animal pharmacology of

reversible antagonism of the gastric acid pump, compared to standard

antisecretory principles. Pharmacology 60, 179–187.

Lachman, L., & Howden, C. W. (2000). Twenty-four-hour intragastric pH:

tolerance within 5 days of continuous ranitidine administration. Am J

Gastroenterol 95, 57–61.

Lambers, C. B., Lind, T., Moberg, S., Jansen, J. B., & Olbe, L. (1984).

Omeprazole in Zollinger–Ellison syndrome. Effects of a single dose

and of long-term treatment in patients resistant to histamine H2-receptor

antagonists. N Engl J Med 310, 758–761.

Lambrecht, N., Munson, K., Vagin, O., & Sachs, G. (2000). Comparison of

covalent with reversible inhibitor binding sites of the gastric H, K-

ATPase by site-directed mutagenesis. J Biol Chem 275, 4041–4048.

Lambrecht, N. W., Yakubov, I., Scott, D., & Sachs, G. (2004, Dec 21).

Identification of the K efflux channel coupled to the gastric H,K ATPase

during acid secretion. Physiol Genomics (electronic publication ahead of

print: http://physiolgenomics.physiology.org/cgi/reprint/00212.2004v1

(accessed 16 February 2005).

Leach, C. A., Brown, T. H., Ife, R. J., Keeling, D. J., Parsons, M. E.,

Theobald, C. J., et al. (1995). Reversible inhibitors of the gastric

(H+/K+)-ATPase: 4. Identification of an inhibitor with an intermediate

duration of action. J Med Chem 38, 2748–2762.

Lindberg, P., Brändström, A., & Wallmark, B. (1987). Structure–activity

relationships of omeprazole and their mechanism of action. Trends

Pharmacol Sci 8, 402.

Lindberg, P., Brandstrom, A., Wallmark, B., Mattsson, H., Rikner, L., &

Hoffmann, K. J. (1990). Omeprazole: the first proton pump inhibitor.

Med Res Rev 10, 1–54.

Long, J. F., Chiu, P. J., Derelanko, M. J., & Steinberg, M. (1983). Gastric

antisecretory and cytoprotective activities of SCH 28080. J Pharmacol

Exp Ther 226, 114–120.

Maeda, M., Oshiman, K., Tamura, S., & Futai, M. (1990). Human gastric

(H++K+)-ATPase gene. Similarity to (Na++K+)-ATPase genes in

exon/intron organization but difference in control region. J Biol Chem

265, 9027–9032.

Makovec, F., Revel, L., Letari, O., Mennuni, L., & Impicciatore, M. (1999).

Characterization of antisecretory and antiulcer activity of CR 2945, a

new potent and selective gastrin/CCK(B) receptor antagonist. Eur J


Malen, C. E., & Danree, B. H. (1971). New thiocarboxamides

derivatives with specific gastric antisecretory properties. J Med Chem

14(3), 244–246.

Malinowska, D. H., Kupert, E. Y., Bahinski, A., Sherry, A. M., &

Cuppoletti, J. (1995). Cloning, functional expression, and character-

ization of a PKA-activated gastric Cl� channel. Am J Physiol 268,C191–C200.

Malinowska, D. H., Sherry, A. M., Tewari, K. P., & Cuppoletti, J.

(2004). Gastric parietal cell secretory membrane contains PKA- and

acid-activated Kir2.1 K+ channels. Am J Physiol Cell Physiol 286,

C495–C506.

Mattsson, J. P., Lorentzon, P., Wallmark, B., & Keeling, D. J. (1993).

Characterization of proton transport in bone-derived membrane

vesicles. Biochim Biophys Acta 1146, 106–112.

McCabe, R. D., & Young, D. B. (1992). Evidence of a K(+)-H(+)-ATPase

in vascular smooth muscle cells. Am J Physiol 262, H1955–H1958.

Mendlein, J., & Sachs, G. (1990). Interaction of a K(+)-competitive

inhibitor, a substituted imidazo[1,2a] pyridine, with the phospho- and

dephosphoenzyme forms of H+,K(+)-ATPase. J Biol Chem 265,

5030–5036.

Metz, D. C., Ferron, G. M., Paul, J., Turner, M. B., Soffer, E., Pisegna,

J. R., et al. (2002). Proton pump activation in stimulated parietal

cells is regulated by gastric acid secretory capacity: a human study.

J Clin Pharmacol 42, 512–519.

Miura, N., Yoneta, T., Ukawa, H., Fukuda, Y., Eta, R., Mera, Y., et al.

(2001). Pharmacological profiles of Z-360, a novel CCK/gastrin

(CCK2) receptor antagonist with excellent oral potency. Gastroenterol-

ogy 120, A311.

Morita, H., Miura, N., Hori, Y., Matsunaga, Y., Ukawa, H., Suda, H., et al.

(2001). Effects of Z-360, a novel CCKB/gastrin (CCK2) receptor

antagonist, on meal-induced acid secretion and experimental ulcer

models in dogs and rats. Gastroenterology 120, A311.

Munson, K. B., Gutierrez, C., Balaji, V. N., Ramnarayan, K., & Sachs, G.

(1991). Identification of an extracytoplasmic region of H+,K(+)-ATPase

http://physiolgenomics.physiology.org/cgi/reprint/00212.2004v1http://physiolgenomics.physiology.org/cgi/reprint/00212.2004v1


labeled by a K(+)-competitive photoaffinity inhibitor. J Biol Chem 266,

18976–18988.

Munson, K., Lambrecht, N., Shin, J. M., & Sachs, G. (2000). Analysis of

the membrane domain of the gastric H(+)/K(+)-ATPase. J Exp Biol

203(Pt 1), 161–170.

Nilsson, C., Albrektson, E., Rydholm, H., Rohss, K., Hassan-Alin, M., &

Hasselgren, G. (2005). Tolerability, pharmacokinetics and effects on

gastric acid secretion after single oral doses of the potassium-

competitive acid blocker AZD0865 in healthy male subjects. Gastro-

enterology 128(4 Suppl. 2), A528.

Nishida, A., Takinami, Y., Yuki, H., Kobayashi, A., Akuzawa, S., Kamato,

T., et al. (1994). YM022 [(R)-1-[2,3-dihydro-1-(2V-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea], a

potent and selective gastrin/cholecystokinin-B receptor antagonist,

prevents gastric and duodenal lesions in rats. J Pharmacol Exp Ther

270, 1256–1261.

Park, S., Song, K., Moon, B. S., Joo, S., Choi, M., & Chung, I., et al.

(2002). The effect of 7 days of dosing with YH1885 on 24-hour

intragastric acidity and plasma gastrin concentration in healthy male

subjects. Gut 51(Suppl 3) (Abstr. TUE-G-312).

Park, S., Ahn, B., Lee, B., Kang, H., & Song, K. (2003a). Pharmacokinetics

of YH1885. Gut 52(Suppl VI).

Park, S., Lee, S., Song, K., Lee, B., Kang, H., & Kang, J. (2003b). The

pharmacological properties of a novel acid pump antagonist, YH1885.

Gut 52(Suppl VI).

Parsons, M. E., Rushant, B., Rasmussen, T. C., Leach, C., Ife, R. J., Postius,

S., et al. (1995). Properties of the reversible, K(+)-competitive inhibitor

of the gastric (H+/K+)-ATPase, SK&F 97574: II. Pharmacological

properties. Biochem Pharmacol 50, 1551–1556.

Pendley, C. E., Fitzpatrick, L. R., Capolino, A. J., Davis, M. A., Esterline,

N. J., Jakubowska, A., et al. (1995). RP 73870, a gastrin/cholecysto-

kinin-B receptor antagonist with potent anti-ulcer activity in the rat.

J Pharmacol Exp Ther 273, 1015–1022.

Pope, A. J., & Parsons, M. E. (1993). Reversible inhibitors of the gastric

H+/K(+)-transporting ATPase: a new class of anti-secretory agent.

Trends Pharmacol Sci 14, 323–325.

Pope, A. J., & Sachs, G. (1992). Reversible inhibitors of the gastric

(H+/K+)-ATPase as both potential therapeutic agents and probes of

pump function. Biochem Soc Trans 20, 566–572.

Pope, A. J., Boehm, M. K., Leach, C., Ife, R. J., Keeling, D., & Parsons, M.

E. (1995). Properties of the reversible K(+)-competitive inhibitor of the

gastric (H+/K+)-ATPase, SK&F 97574: I. In vitro activity. Biochem

Pharmacol 50, 1543–1549.

Prinz, C., Kajimura, M., Scott, D. R., Mercier, F., Helander, H. F., & Sachs,

G. (1993). Histamine secretion from rat enterochromaffinlike cells.

Gastroenterology 105, 449–461.

Prinz, C., Scott, D. R., Hurwitz, D., Helander, H. F., & Sachs, G. (1994).

Gastrin effects on isolated rat enterochromaffin-like cells in primary

culture. Am J Physiol 267, G663–G675.

Rabon, E. C., & Reuben, M. A. (1990). The mechanism and structure of the

gastric H,K-ATPase. Annu Rev Physiol 52, 321–344.

Rabon, E. C., Smillie, K., Seru, V., & Rabon, R. (1993). Rubidium

occlusion within tryptic peptides of the H,K-ATPase. J Biol Chem 268,

8012–8018.

Rajendran, V. M., Singh, S. K., Geibel, J., & Binder, H. J. (1998).

Differential localization of colonic H(+)-K(+)-ATPase isoforms in

surface and crypt cells. Am J Physiol 274, G424–G429.

Reenstra, W. W., & Forte, J. G. (1990). Characterization of K+ and Cl�conductances in apical membrane vesicles from stimulated rabbit

oxyntic cells. Am J Physiol 259, G850–G858.

Ritter, M., Schratzberger, P., Rossmann, H., Woll, E., Seiler, K., Seidler,

U., et al. (1998). Effect of inhibitors of Na+/H+-exchange and

gastric H+/K+ ATPase on cell volume, intracellular pH and

migration of human polymorphonuclear leucocytes. Br J Pharmacol

124, 627–638.

Robinson, M., & Shaw, K. (2002). Proton pump inhibitor attitudes and

usage: a patient survey. Pharm Ther J 27, 202–206.

Rottapharm. (2004). CR2945 (Itriglumide) Product profile. Available at:

http://www.rotta.com/cr2945.htm. Accessed December 17, 2004.

Sachs, G. (1994). The gastric H+,K+-ATPase. In L. R. Johnson (Ed.),

Physiology of the Gastrointestinal Tract (pp. 1119–1138). New York’

Raven Press.

Sachs, G., Shin, J. M., Briving, C., Wallmark, B., & Hersey, S. (1995). The

pharmacology of the gastric acid pump: the H+,K+ ATPase. Annu Rev

Pharmacol Toxicol 35, 277–305.

Salas, M., Ward, A., & Caro, J. (2002). Are proton pump inhibitors the first

choice for acute treatment of gastric ulcers? A meta analysis of

randomized clinical trials. BMC Gastroenterol 2, 17.

Sangan, P., Rajendran, V. M., Mann, A. S., Kashgarian, M., & Binder, H. J.

(1997). Regulation of colonic H-K-ATPase in large intestine and kidney

by dietary Na depletion and dietary K depletion. Am J Physiol 272,

C685–C696.

Scott, C. K., Sundell, E., & Castrovilly, L. (1987). Studies on the mechanism

of action of the gastric microsomal (H++K+)-ATPase inhibitors SCH

32651 and SCH 28080. Biochem Pharmacol 36, 97–104.

Selby, N. M., Kubba, A. K., & Hawkey, C. J. (2000). Acid suppression in

peptic ulcer haemorrhage: a Fmeta-analysis_. Aliment Pharmacol Ther

14, 1119–1126.

Sohn, S. K., Chang, M. S., Choi, W. s., Chung, Y. K., Kim, K. B., Woo, T.

W., et al. (1999). Biochemical and pharmacological characteristics of a

newly synthesized H+/K+-ATPase inhibitor, YJA20379-8, 3-butyryl-4-

[R-1-methylbenzylamino]-8-ethoxy-1,7-naphthyridine, in pigs and rats.

J Pharm Pharmacol 51, 1359–1365.

Steel, K. (2002). Gastrin and gastrin receptor ligands—a review of recent

patent literature. IDrugs 5, 689–695.

Swarts, H. G., Hermsen, H. P., Koenderink, J. B., Schuurmans Stekhoven,

F. M., & de Pont, J. J. (1998). Constitutive activation of gastric H+,K+-

ATPase by a single mutation. EMBO J 17, 3029–3035.

Takeuchi, K., Hirata, T., Yamamoto, H., Kunikata, T., Ishikawa, M., &

Ishihara, Y. (1999). Effects of S-0509, a novel CCKB/gastrin receptor

antagonist, on acid secretion and experimental duodenal ulcers in rats.

Aliment Pharmacol Ther 13, 87–96.

Tefera, S., Hatlebakk, J. G., & Berstad, A. (2001). Stability of gastric

secretory inhibition during 6-month treatment with omeprazole in

patients with gastroesophageal reflux disease. Am J Gastroenterol 96,

969–974.

Tsukimi, Y., Ushiro, T., Yamazaki, T., Ishikawa, H., Hirase, J.,

Narita, M., et al. (2000). Studies on the mechanism of action of

the gastric H+,K(+)-ATPase inhibitor SPI-447. Jpn J Pharmacol 82,

21–28.

Ushiro, T., Tsukimi, Y., & Tanaka, H. (1997). Inhibition of gastric

H+, K+-ATPase by 3-amino-5-methyl-2-(2-methyl-3-thienyl)imi-

dazo[1,2-a]thieno[3,2-c]pyridine, SPI-447. Jpn J Pharmacol 75,

303–306.

Vagin, O., Munson, K., Lambrecht, N., Karlish, S. J., & Sachs, G. (2001).

Mutational analysis of the K+-competitive inhibitor site of gastric H,K-

ATPase. Biochemistry 40, 7480–7490.

Vagin, O., Denevich, S., Munson, K., & Sachs, G. (2002). SCH28080, a

K+-competitive inhibitor of the gastric H,K-ATPase, binds near the M5-

6 luminal loop, preventing K+ access to the ion binding domain.

Biochemistry 41, 12755–12762.

Vagin, O., Munson, K., Denevich, S., & Sachs, G. (2003). Inhibition

kinetics of the gastric H,K-ATPase by K-competitive inhibitor

SCH28080 as a tool for investigating the luminal ion pathway. Ann N

Y Acad Sci 986, 111–115.

Vakil, N. (2004). Review article: new pharmacological agents for the

treatment of gastro-oesophageal reflux disease. Aliment Pharmacol

Ther 19, 1–9.

Vander Stricht, D. V., Raussens, V., Oberg, K. A., Ruysschaert, J. M.,

& Goormaghtigh, E. (2001). Difference between the E1 and E2

conformations of gastric H+/K+-ATPase in a multilamellar lipid

film system. Characterization by fluorescence and ATR-FTIR

spectroscopy under a continuous buffer flow. Eur J Biochem 268,

2873–2880.

http://www.rotta.com/cr2945.htm


van Driel, I. R., & Callaghan, J. M. (1995). Proton and potassium transport

by H+/K(+)-ATPases. Clin Exp Pharmacol Physiol 22, 952–960.

van Pinxteren, B., Numans, M. E., Bonis, P. A., & Lau, J. (2001). Short-

term treatment with proton pump inhibitors, H2-receptor antagonists

and prokinetics for gastro-oesophageal reflux disease-like symptoms

and endoscopy negative reflux disease. Cochrane Database Syst Rev

(CD002095).

van Pinxteren, B., Numans, M. E., Lau, J., de Wit, N. J., Hungin, A. P., &

Bonis, P. A. (2003). Short-term treatment of gastroesophageal reflux

disease. J Gen Intern Med 18, 755–763.

Wallmark, B., Briving, C., Fryklund, J., Munson, K., Jackson, R.,

Mendlein, J., et al. (1987). Inhibition of gastric H+,K+-ATPase and

acid secretion by SCH 28080, a substituted pyridyl(1,2a)imidazole.

J Biol Chem 262, 2077–20784.

Watts, J. A., Watts, A., & Middleton, D. A. (2001). A model of

reversible inhibitors in the gastric H+/K+-ATPase binding site

determined by rotational echo double resonance NMR. J Biol Chem

276, 43197–43204.

Wurst, W., & Hartmann, M. (1996). Current status of acid pump antagonists

(reversible PPIs). Yale J Biol Med 69, 233–243.

Yan, D., Hu, Y. D., Li, S., & Cheng, M. S. (2004). A model of 3D-structure

of H+, K+-ATPase catalytic subunit derived by homology modeling.

Acta Pharmacol Sin 25, 474–479.

Yu, K. S., Bae, K. S., Shon, J. H., Cho, J. Y., Yi, S. Y., Chung, J. Y., et al.

(2004). Pharmacokinetic and pharmacodynamic evaluation of a novel

proton pump inhibitor, YH1885, in healthy volunteers. J Clin


本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具

http://www.xuebalib.com/cloud/http://www.xuebalib.com/http://www.xuebalib.com/cloud/http://www.xuebalib.com/http://www.xuebalib.com/vip.htmlhttp://www.xuebalib.com/db.phphttp://www.xuebalib.com/zixun/2014-08-15/44.htmlhttp://www.xuebalib.com/

Potassium-competitive acid blockade: A new therapeutic strategy in acid-related diseasesIntroductionPhysiology of acid secretionStructure and properties of gastric H+,K+-ATPaseTargeting gastric acid secretionH2 receptor antagonists and H3 receptor agonistsMuscarinics and cholecystokinin2 receptor antagonistsProton pump inhibitors

Potassium-competitive acid blockersDevelopment of the potassium-competitive acid blocker classMechanism of potassium-competitive acid blocker inhibition of gastric H+,K+-ATPaseSelectivity of potassium-competitive acid blockers for gastric H+,K+-ATPasePharmacokinetics of potassium-competitive acid blockersPharmacodynamics of potassium-competitive acid blockersPharmacodynamic comparisons of potassium-competitive acid blockers with other agents

SummaryReferences

potassium-competitive acid blockade: a new therapeutic...

Documents