Done By: Ali H. AbbasMsc StudentPharmaceutical Chemistry Department

PROTON PUMP INHIBITORS

DISCOVERY AND DEVELOPMENT

HISTORY OF DISCOVERY:

Evidence emerged by the end of the 1970s that the newly discovered proton pump (H+,K+-ATPase) in the secretory membrane of the parietal cell was the final step in acid secretion. Literature from anaesthetic screenings led attention to the potential antiviral compound pyridylthioacetamide which after further examination pointed the focus on an anti-secretory compound with unknown mechanisms of action called timoprazole. Timoprazole is apyridylmethylsulfinyl benzimidazole and appealed due to its simple chemical structure and its surprisingly high level of anti-secretory activity.

BASIC STRUCTURE:

PPIs can be split into two groups based on their basic structure. Though all have a substituted pyridine part, first group has linked to various

benzimidazoles.Second group has linked to a substituted

imidazopyridine.

TEMOPRAZOLE:

In the year 1975, timoprazole was found to inhibit acid secretion irrespective of stimulus, extracellular or intracellular.Studies on timoprazole revealed enlargement of the thyroid gland due to inhibition of iodine uptake as well as atrophy of the thymus gland. A literature search showed that some substituted mercapto-benzimidazoles had no effect on iodine uptake and introduction of such substituents into timoprazole resulted in an elimination of the toxic effects, without reducing the antisecretory effect.

The first step shows protonation of the pyridine ring and the benzimidazole ring inside theparietal cell. The protonated molecule cannot leave the cell any more. The last group of steps shows the active forms, a permanent tetracyclic sulfenic acid along with its dehydrated form of a sulfenamide, and how either of those can form disulfides with one or more H+/K+-ATPase cysteins accessible from the luminal surface of the enzyme.

OMEPRAZOLE:

A derivative of timoprazole, omeprazole, was discovered in 1979, and was the first of a new class of drug that control acid secretion in the stomach, a proton pump inhibitor (PPI). Addition of 5-methoxy-substitution to the benzimidazole moiety of omeprazole was also made and gave the compound much more stability at neutral pH.

Omeprazole was the first PPI on the market, in 1988. It is a 1:1 racemate drug with a backbone structure of timoprazole, but substituted with two methoxy and two methyl groups: the methoxy group one at position 6 of

the benzimidazole and the other at position 4 of the pyridine.

the methyl groups are at position 3 and 5 of the pyridine.

LANSOPRAZOLE:

Lansoprazole was the second of the PPI drugs to reach the market, being launched in Europe in 1991 and the US in 1995. It has no substitutions at the benzimidazole but two substituents on the pyridine: methyl group at position 3.trifluoroethoxy group at position 4.The drug is a 1:1 racemate of the enantiomers dexlansoprazole and levolansoprazole.

The story of pantoprazole's discovery is a good example of the stepwise development of PPIs. The main focus of modification of timoprazole was the benzimidazole part of its structure. Addition of a trifluoromethyl group to the benzimidazole moiety led to a series of very active compounds with varying solution-stability. In general fluoro substituents were found to block metabolism at the point where they were attached. Later the more balanced fluoroalkoxy substituent, instead of the highly lipophilic and strongly electron-withdrawing trifluoromethyl substituent, led to highly active compounds with supposed longer half-lives and higher solution stability.

PANTOPRAZOLE:

Pantoprazole was the third PPI and was introduced to the German market in 1994. It has a difluoroalkoxy sidegroup on the benzimidazole part and two methoxy groups in position 3 and 4 on the pyridine. Pantoprazole was first prepared in April 1985 by a small group of scale-up chemists.

RABEPRAZOLE:

Rabeprazole is a novel benzimidazole compound on market, since 1999 in USA. It is similar to lansoprazole in having no substituents on its benzimidazole part and a methyl group at site 3 on the pyridine, the only difference is the:methoxypropoxy substitution at site 4 instead of the trifluoroethoxy group on lansoprazole. Rabeprazole is marketed as rabeprazole sodium salt.

DEVELOPMENT OF ESOMEPRAZOLE

Omeprazole showed an inter-individual variability and therefore a significant number of patients with acid-related disorders required higher or multiple doses to achieve symptom relief and healing. Astra started a new research program in 1987 to identify a new analogue to omeprazole with less interpatient variability. Only one compound proved superior to omeprazole and that was the S-isomer, esomeprazole, which was developed as the magnesium salt.

Esomeprazole magnesium (Nexium) received its first approval in 2000 and provided more pronounced inhibition of acid secretion and less inter-patient variation compared to omeprazole. In 2004, Nexium had already been used to treat over 200 million patients.

DEXLANSOPRAZOLE:

Dexlansoprazole was launched as a follow up of lansoprazole in 2009. dexlansoprazole is an R-enantiomer of lansoprazole, marketed as Dexilant. After oral appliance of the racemic lansoprazole, the circulating drug is 80% dexlansoprazole. Moreover, both enantiomers have similar effects on the proton pump

IMIDAZOPYRIDINES: 

TenatoprazoleTenatoprazole (TU-199), an imidazopyridine proton pump inhibitor, is a novel compound that has been designed as a new chemical entity with a substantially prolonged plasma half-life (7h), but otherwise has similar activity as other PPIs. The difference in the structural backbone of tenatoprazole compared to benzimidazole PPIs, is its imidazo[4,5-b]pyridine moiety, which reduces the rate of metabolism, allowing a longer plasma residence time but also decreases the pKa of the fused imidazole N as compared to the current PPIs.  

Tenatoprazole has the same substituents as omeprazole, the methoxy groups at position 6 on the imidazopyridine and at position 4 on the pyridine part as well as two methyl groups at position 3 and 5 on the pyridine. The bioavailability of tenatoprazole is double for the S-tenatoprazole sodium salt hydrate form when compared to the free form in dogs. This increased bioavailability is due to differences in the crystalstructure and hydrophobic nature of the two forms, and therefore its more likely to be marketed as the pure S-enantiomer

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