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Hugo Kubinyi, www.kubinyi.de
Peptidomimeticsand Prodrugs
Hugo Kubinyi
Germany
E-Mail kubinyi@t-online.deHomePage www.kubinyi.de
Hugo Kubinyi, www.kubinyi.de
Endogeneous peptidictransmitters
Function
Leu-enkephalin, Met-enkephalin
Ligands of the morphine receptor (analgesics)
Angiotensin II Blood pressure regulationEndothelin Blood pressure regulationNeuropeptide Y Blood pressure regulationSubstance P Different effects, e.g. broncho-
constriction, pain signallingFibrinogen Blood platelet aggregation
Physiological Role of Peptides
Hugo Kubinyi, www.kubinyi.de
NO
Me
NO
Me
O
N
N NMe
NMe
NMe
NMe
O
O
OO
NOO
N
ONMe
OOH
H-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2Oxytocin (labor induction)
Cyclosporin A (immunosuppressant)
pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEtLeuprolide (LHRH analog, prostate cancer)
H H
H
H
Peptide Drugs
Hugo Kubinyi, www.kubinyi.de
COOH
NH2
COOH
NH2 COOHNH2
COOH
NH2
ααααββββ
PhenylalanineN
O
N
O
ω φ
χ
ψ
CγγγγCββββ
Cαααα
H
H
Phenylalanine and Some Analogs
Hugo Kubinyi, www.kubinyi.de
COOH
NH
N COOH NHNH2
O
NHNH2
ONH
O
NH2
NH2 COOH
F
NH2 COOH
OCH3
NH2 COOH
CH3
CH3
H
NH2 COOHCH3
Other Phenylalanine Analogs
Hugo Kubinyi, www.kubinyi.de
H OH R
R R
N-methyl ketomethylene hydroxyethylene
PX
O O R
O R
phosphonamide, phosphonate, phosphinate; X = -NH-, -O-, -CH2-retro-inverso
N
O
R
N
O
CH3
R
ether reduced amideH
H
N
R
O
R
(E)-ethylene carba
Replacement of the Peptide Bond
Hugo Kubinyi, www.kubinyi.de
NNO
O
RNO
N
OOR
R
N
N
RN
N
O
N
RN
NNN
R
O
S
N
S
NO O
N
N
NO
O
HH
H
H
H H
H
Conformational Stabilization by Cyclisation
Hugo Kubinyi, www.kubinyi.de
Protein Secondary Structure Elements: ß turns
Hugo Kubinyi, www.kubinyi.de
NO
N
SH
O
N
S
O
H
H
O
N
N
N
R
O
R
O
SNH
O
NH O
O
S
NHO
OO
H
H
ONH
NH O
NHO
O
Nφφφφi+1
ψψψψi+1 φφφφi+2
ψψψψi+2
(i)(i+3)
Ri
Ri+2
Ri+3
Ri+1
H
ß-Turn 3D Structure and ß-Turn Mimetics
Hugo Kubinyi, www.kubinyi.de
Structure Ki [nM]
Substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2
295
Active analog Leu-Gln-Met-Trp-Phe-Gly-NH2 11.7
Ala scan Ala-Gln-Met-Trp-Phe-Gly-NH2 40
Leu-Ala-Met-Trp-Phe-Gly-NH2 138
Leu-Gln-Ala-Trp-Phe-Gly-NH2 156
Leu-Gln-Met-Ala-Phe-Gly-NH2 >10,000
Leu-Gln-Met-Trp-Ala-Gly-NH2 8,300
Leu-Gln-Met-Trp-Phe-Ala-NH2 28
Leu-Gln-Met-Trp-Phe-NH2 200
Dipeptide Z-Trp-Phe-NH2 2,700
Rational Design of NK2 Receptor Antagonists
Hugo Kubinyi, www.kubinyi.de
Rational Design of NK2 Receptor AntagonistsStructure Ki [nM]
Dipeptide Z-Trp-Phe-NH2 2,700
Stabilize the bioactiveconformation
Z-Trp-(R,S)-(αααα-Me)Phe-NH2 327
Optimize theN-terminus
(2,3-di-OCH3)C6H3-CH2OCO-Trp-(R,S)-(αααα-Me)Phe-NH2
37.6
Find activeenantiomer
(2,3-di-OCH3)C6H3CH2OCO-Trp-(R)-(αααα-Me)Phe-NH2
10,000
(2,3-di-OCH3)C6H3CH2OCO-Trp-(S)-(αααα-Me)Phe-NH2
17.2
Attach additionalgroup
(2,3-di-OCH3)C6H3CH2OCO-Trp-(S)-(αααα-Me)Phe-Gly-NH2
1.4
Hugo Kubinyi, www.kubinyi.de
Rational Design of NK2 Receptor Antagonists
N
O N
ON
O
O
NH2R
Ki = 2,700 nM
Ki = 327 nM
Ki = 1.4 nM
N
O N
ON
O
OOO NHR
Ki = 17.2 nM
R = H
R = CH3
R = H
R = CH2CONH2
H
H
H
H
H
H
Hugo Kubinyi, www.kubinyi.de
Optimization of an NK1 Receptor Antagonist
N
N O
O
R
R = H, X = H IC50 >10,000 nM
X
R = Et, X = H IC50 = 3,800 nM
R = H, X = 3,5-di-CH3 IC50 = 1,533 nMR = Ac, X = 3,5-di-CH3 IC50 = 67 nMR = Ac, X = 3,5-di-CF3 IC50 = 1.6 nM
N
NO
CF3
CF3CH3
O
orally available analog
IC50 = 3 nM
H
HH
H
Hugo Kubinyi, www.kubinyi.de
A Small Molecule Insulin Mimetic
O
O
OH
OH
NH
NH
L-783,281
O
O
OH
OH
NH
NH
L-767,827
screening of > 50,000 mixtures of synthetics and natural products yielded the insulin mimetic L-783,281
3-6 µM produce 50% increase of the maximal effect of insulin (in mice)
less active by afactor of 100
B. Zhang et al., Science 284, 974-977 (1999)
Hugo Kubinyi, www.kubinyi.de
N
NHN
O
O
NN O
OH
H
H
N
OCH3
N
HN N
O
Asperlicin(microbial product) ED50 i.v. = 14.8 mg/kg ED50 p.o. > 300 mg/kg
Devazepide, L-364 718
ED50 i.v. = 0.01 mg/kgED50 p.o. = 0.04 mg/kg
H
H
H
N
N
O
HH
N NOH
O
Ki CCK-A (rat) = 1,480 nMKi CCK-B (human) = 0.15 nM
H H
GV 150 013
Ki CCK-A (rat) = 0.37 nMKi CCK-B (human) = 29.5 nM
cf.
CCK-A and CCK-BAntagonists
A. Ursini et al., J. Med. Chem. 43, 3596-3613 (2000)
Hugo Kubinyi, www.kubinyi.de
Design of an Orally Active TRH Mimetic
N
O
O CONH2
N
N
N
NHO
TRH
H
H
metabolically not stable,no oral bioavailability
N
N
CONH2NO
Ph
H
peptidomimetic,orally bioavailable,sufficient half-life time
G. L. Olson et al., J. Med. Chem. 36, 3039-3049 (1993)
Hugo Kubinyi, www.kubinyi.de
Amino Acid Amides as Somatostatin Mimics
NH
NH
N
O NH
NH2R
O
sst2 Ki = 5.9 nM
sst1 Ki = 3,794 nMsst2 Ki = 1.0 nMsst3 Ki = 360 nMsst4 Ki = 2,402 nMsst5 Ki = 2,105 nM
R = H
R = COOMe
NH
NH
N
O NH
NH2t-BuOOC
O
MeN
NHO
sst1 Ki = 2,392 nMsst2 Ki = 0.01 nMsst3 Ki = 31 nMsst4 Ki = 81 nMsst5 Ki = 163 nM
L. Yang et al., Proc. Natl. Acad. Sci. USA 95, 10836-10841 (1998)
Hugo Kubinyi, www.kubinyi.de
A Nonpeptidic Somatostatin Mimic
O
OO
OO
NH2
NH3-deoxy-glucose
mimic of the receptor-recognizing ß-turnPhe7-Trp8-Lys9-Thr10of somatostatin.
IC50 = 1.3 µM (pituitarysomatostatin receptor)
agonist activity in afunctional assay at 3 µM
K. C. Nicolaou et al., Peptide Chem. Struct. Biol., Proceedings of the 11th Am. Peptide Symp., 1990, pp. 881-884; C. Wermuth, The Practice of Medicinal Chemistry, 1996, pp. 571 ff.
Hugo Kubinyi, www.kubinyi.de
A Subtype-Specific Somatostatin Mimic
O
O RO
OO
NH2
NH
O
glucose
R = phenyl non-selective, weak sst-receptor partial agonist
R = imidazol-4-yl 100 nM, selective sst4-receptor agonist
R. Hirschmann et al., J. Med.Chem. 41, 1382-1391 (1998).
Hugo Kubinyi, www.kubinyi.de
NN
O
O COOH
COOH
NH2
NH
N
OCOOEt
NH2
NH
NN
N
OCOOEt
NH2
NH
O
NH2
NH
N NN
NNH2
O
O
O COOH
COOHH H H
H
H
H
HH
H
RGD motif, thebinding domainof integrinreceptor ligands
Stepwise Design of Nonpeptidic, Orally AvailableFibrinogen Receptor Antagonists
Hugo Kubinyi, www.kubinyi.de
Rational Design of Integrin Receptor Ligands
NH
N
ON
N
NH2COOH
O
N
NH
NH2
S SNHN O O
N NO
OCOOH
CH3
H
H
H
H
H
O
NH
NH
ONHO
O
N
COOHNH
O
NNH2
NH
H
H
cyclo(RGDFv)
(v = D-Valine)
R G D
Fv
Ki = 2.0 nM
Ki = 2.3 nM
Hugo Kubinyi, www.kubinyi.de
Superposition of Integrin Receptor Ligands
Hugo Kubinyi, www.kubinyi.de
N
O
N
NO
COOH
NH
NH2H
HN
NCH3
O
O
NN
X COOH
X = NKi GPIIb/IIIa = 8 nMKi ααααvββββ3 = 1,000 nM
X = CHKi GPIIb/IIIa >100,000 nMKi ααααvββββ3 = 9,200 nM
m-amidineKi GPIIb/IIIa = 4,500 nMKi ααααvββββ3 = 510 nM
p-amidineKi GPIIb/IIIa = 26 nMKi ααααvββββ3 = 56,000 nM
H
Selectivity of Integrin Receptor Ligands
Hugo Kubinyi, www.kubinyi.de
HN
N
COOH
CH3
O
O
N
NH
lotrafiban (SB 214 857) Ki GPIIb/IIIa = 2.5 nMKi ααααvββββ3 = 10,340 nM
HN
N
COOH
CH3
O
O
NCH3
N
NH
SB 223 245Ki GPIIb/IIIa = 30,000 nMKi ααααvββββ3 = 2 nM
Highly Selective Integrin Receptor Ligands
Lotrafiban failed in phase III, due to lack of activity and increased mortality (J.-M. Dogné et al., Curr. Med. Chem. 9, 577-589 (2002))
Hugo Kubinyi, www.kubinyi.de
CrystalStructure of the ExtracellularSegment ofIntegrin ααααvß3;complex with cyclo-RGDf-N-MeV
J.-P. Xionget al., Science296, 151-155(2002)
Hugo Kubinyi, www.kubinyi.de
Binding Mode ofcyclo-RGDf-N-MeVto the Extracellular Segment of Integrin ααααvß3
Hugo Kubinyi, www.kubinyi.de
Prodrugs, Soft Drugs and Targeted DrugsProdrugs are inactive (or less active) drug analogs that have better pharmacokinetic properties (e.g.oral bioavailability, BBB penetration) than theirparent drugs. They are (specifically) metabolized to the active form of the drug.Soft drugs are biologically active derivatives of inactive drug analogs , e.g. esters of corticosteroidcarboxylic acids. These esters are (topically) active;after dermal absorption they are readily degraded by metabolic enzymes to inactive analogs.Targeted drugs are drugs or prodrugs that exert their biological action only in certain organs or cells (e.g. Omeprazole, Aciclovir).
Hugo Kubinyi, www.kubinyi.de
Bile, Feces(lipophiliccompounds)
Drug
Metabolites
Metabolites
Gastric/intestinal wall
Portal vein
Organs
Kidneys
Urine (polar compounds)
Cardio-vascularsystem
Liver
Distribution and Metabolism of Drugs in a Biological System
Hugo Kubinyi, www.kubinyi.de
O
CH3COO
CH3COO
N CH3
HH
heroin
Cl
O
CH3 CH3
OR
O
clofibrate, R = Etclofibric acid, R = H
OH H
NH
ORH
O
CHCl2
chloramphenicol (bitter taste), R = H
tasteless prodrug R = CO(CH2)14CH3
O2N
Prodrugs: Esters
Hugo Kubinyi, www.kubinyi.de
Aspirin®, a Prodrug?(Felix Hoffmann, 1897)
OCOCH3
COOH
OH
COOH
Hugo Kubinyi, www.kubinyi.de
OCOOH
CH3
OH
SCoA
OHCOOH
CH3
OHHMG-CoA reductase
HMG-CoAmevalonic acid
O
HOH O
R lovastatin active metabolite
OHCOOH
HOH
R
N NH2
O
F
OH
Cl
blood brainbarrier
NH2 OH
O
progabide
GABA
Prodrugs: Lactones and Amides
Hugo Kubinyi, www.kubinyi.de
Prodrugs: Hydrazides and Azo Compounds
NH2 N N
NH2
SO2NH2
NH2 SO2NH2 NH2 COOH
sulfamidochrysoidine ("prontosil rubrum")
sulfanilamide, an antimetabolite of p-aminobenzoic acid
metabolicdegradation
cf.
N
ROthe metabolite isonicotinic acid(R = -OH) is anantimetabolite ofnicotinic acid
nicotinic acid
N
COOHisoniazide,R = -NH-NH2(tuberculostatic)
Hugo Kubinyi, www.kubinyi.de
N N N
NH NH CH3
CH3
Cl
N N
N
Cl
NH2 NH2
CH3 CH3
bioactivation
proguanil cycloguanil
HHH
Other ProdrugsS
CH3
F
CH3
CH2COOH
O
sulindacS
CH3
F
CH3
CH2COOH
bioactivation
Hugo Kubinyi, www.kubinyi.de
OHN
CH3
RO
RO
Dipivefrine, R = COC(CH3)3
Epinephrine, R = H
SNN
N
O
O NX
CH3
CH3
CH3
Oxime ether, X = N-OCH3
Ketone, X = O
Timolol, X = H, OH
HH
Dipivefrine is 20x faster metabolized in the eye than in the periphery. The timolol prodrug is only metabolized in the eye. Both prodrugs are used for the therapy of glaucoma.
Drug Targeting into the Eye
Hugo Kubinyi, www.kubinyi.de
Kidney-Selective Release of Sulfamethoxazole
NH
O
NH
O
Me
SNH
NO
Me
OO
COOH
1) N-acylamino acid deacylase
2) γγγγ-glutamyl transpeptidase NH2
SNH
NO
Me
OO
both enzymes are present inhigh concentration in the kidney
C. G. WermuthThe Practiceof MedicinalChemistry, Academic Press,New York 1996, pp. 684-685
Hugo Kubinyi, www.kubinyi.de
NCH3
NCH3+
NCH3+
+
enzymaticoxidation
NCH3
R
MPTP toxic metabolitesPethidine, R = COOEtMPPP, R = OCOEt
1-methyl-4-phenyl-4-propionyloxy-piperidine (MPPP) corresponds to pethidine but a “leaving group” results. Consumption of impure material leads to severe Parkinson symptoms, followed by early death. MPTP is a “prodrug” of permanently charged cytototoxic metabolites. The MAO inhibitor selegilin prevents this oxidation.
Drug Abuse Leads to a New Prodrug Concept
Hugo Kubinyi, www.kubinyi.de
N
X drug
O
CH3
H Hperiphery blood brain barrier brain
N
X drug
O
CH3
H H
N
X drug
O
CH3
+ N
X drug
O
CH3
fastelimination
metabolic cleavage
freedrug
metabolic activation
+
neutral,lipophilic
charged,polar form
Brain Targeting of Drugs
However,
!!!! ?
Hugo Kubinyi, www.kubinyi.de
Omeprazole Case Study
O NH
OO
NNH2
S
NS
NH
N NSO
NH
N
1966: Local anesthetics reduce gastric secretion (Hässle)1966-1972: First lead1972-1979: New lead pyridyl- acetamide (from screening of antiviral compounds) Active analogs; metabolite with higher antisecretory activity
Hugo Kubinyi, www.kubinyi.de
Picoprazole, 1976preclinical candidate
Omeprazole Case Study
Tox study:
vasculitis
picoprazole group placebo group
breeding dogFabian
OS
NH
NMeOOC
MeN
Me
Hugo Kubinyi, www.kubinyi.de
N
NS
N
O
CH3OMe
CH3
MeO
N
N
S
N
OH
CH3OMe
CH3MeO
+H+
N
NN
S
CH3
OMe
CH3
MeO
+ATPase-SH
N
NN
CH3
OMe
CH3S
S
MeO
+
ATPase
omeprazole
H
H
H
Drug Activation in Acid-Producing Cells - A Serendipitous Discovery of a Targeted Drug
Hugo Kubinyi, www.kubinyi.de
Omeprazole Activation in Acid-Producing Cells
Distribution ofradio-labelledomeprazole,one minute afteri.v. injection, rat
sixteen hours after i.v. injection, rat
courtesy of Dr. K. Andersson, AstraZeneca, Sweden
liverstomachkidney
Hugo Kubinyi, www.kubinyi.de
Omeprazole Activation in Acid-Producing Cells
Distribution ofradio-labelledomeprazole,one minute afteri.v. injection, rat
sixteen hours after i.v. injection, rat
courtesy of Dr. K. Andersson, AstraZeneca, Sweden
liverstomachkidney
Hugo Kubinyi, www.kubinyi.de
NN
O COOH
CH3
ROOC
enalapril, R = Et
enalaprilate, R = HN
R2
N
O
O
R1
EtOOC
diketopiperazine
R1 = phenethyl, R2 = MeH
NH2OH
OH
NH2OH
OH COOHdopamine L-dopa
Use of the AA and Dipeptide Transporters
Hugo Kubinyi, www.kubinyi.de
O
NHP N
Cl
Cl
O
O
NHP N
Cl
Cl
O
OH
Cyclophosphamide
NHCl
Cl NH-Lost acrolein
O
Mustard gas
N-Lost, R = CH3SCl
ClN
Cl
ClR
N-Aryl-Lost, R = Aryl
metabolic activation in the liver
+
Pro-Prodrugs
Hugo Kubinyi, www.kubinyi.de
CH3 NH2
N
OOH
OH
COOHH
αααα-Methyldopa-Phe
CH3
NH2OH
OH
OH
αααα-Methylnorepinephrine
The dipeptide αααα-Methyldopa-Phe is readily absorbed as a substrate of the dipeptide transporter. In the first pass, αααα-Methyldopa is produced, a substrate of the amino acid transporter. Transport into the brain, decar-boxylation and hydroxylation produces a „false neuro-transmitter“, the α α α α2 agonist αααα-Methylnorepinephrine.
A Most Elegant Prodrug Concept
Hugo Kubinyi, www.kubinyi.de
NH
N N
N
NH2
O
OOH
NH
N N
N
NH2
O
OO
ONH2
MeMe
valaciclovir,a pro-prodrug
NH
N N
N
NH2
O
OO-P
aciclovir
1) monophosphorylation by viral thymidine kinase
2) phosphorylation by cellular kinase
NH
N N
N
NH2
O
OO-P-P-P
DNA polymerase inhibition (chain termination)
Antiviral Prodrugs are Trojan Horses
Hugo Kubinyi, www.kubinyi.de
famciclovir
N
N N
N
NH2 OAc
OAc penciclovir
NH
N N
N
NH2 OH
OH
O
triphosphate(active form; DNA chain termination)
zidovudine(azidothymidine, AZT)
NH
N
O
O
Me
OOH
N3
intracellularphosphorylation
triphosphate(inhibits reverse transcriptase; inactive against incorporated viruses)
Antiviral Prodrugs are Trojan Horses
Hugo Kubinyi, www.kubinyi.de
NH
N
O
O
F
5-fluorouracilH
NH
N
O
O
F
O
OH
OH
NH
N
O
O
F
O
OH
O-P-P-P
5-F-uridylate
NH
N
NH
O
F
O
OH
Me
OH
O
OMe
capecitabine orally active prodrug, tumour-specific activation by a cascade of enzymes:1) carboxypeptidase cleavage (liver)2) cytidine deaminase (liver, tumours)3) thymidine phosphorylase (tumours)
(a thymidylate synthase inhibitor)
Prodrugs of Site-Specific Trojan Horses
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