Anti-ulcer Agents

Anti-Ulcer Agents Michael Alwan November 11, 2004 Medicinal Chemistry. Southern Methodist Univ.

What is Peptic Ulcer? 

An Ulcer is … 

Localized erosion in stomach or duodenum

Symptoms and Causes 

What are the symptoms of a peptic ulcer? Burning pain in the gut  Starts 2/3 hours after meals, or in the middle of the night 



What causes peptic ulcers? Non-Steriodal Anti-Inflammatory Drugs (NSAIDS)  Helicobacter pylori 

Rational Approach to Drug Design 

Histamine 2 Receptors 



Proton Pump Inhibitors 



Tagamet, Zantac, Pepcid, Axid Protonix, Prilosec, Prevacid, Aciphex, Nexium

Antibiotics 

Clarithromycin, Amoxycillan, Tetracyclin

H2 Receptor 

Histamine receptor on parietal cells 



Autonomic system: food stimulates gastrin release, gastrin stimulates ECL cells, stimulates histamine release, histamine stimulates parietal cells secretion of HCl

2 histamine receptors? 

If histamine stimulates acid secretion why do antihistamines fail to inhibit other actions of histamine? The possibility of a second histamine receptor …

H2 Receptor Antagonist 

Must bind but not activate H2 receptor site 

 

Addition of a functional group to bind with another binding region and prevent the conformational change Addition of aromatic ring: unsuccessful Addition of non-polar, hydrophobic substituents, none antagonists, but …

4-methylhistamine 

Not an antagonist, but highly H2 selective 

Conformational isomers show preferential binding

4-methylhistamine Conformation I

4-methylhistamine Conformation II

Nα -Guanylhistamine 

First partial agonist

First signs of antagonistic activity  Still allows partial conformational change 

α N -Guanylhistamine  Guanidine present in A.A. residue arginine

Carbon chain lengthened 

Two-carbon chain, speculation of a carboxylate binding region



Three-carbon chain, speculation of different binding region

Burimamide 

Enhanced antagonist activity  

Longer chain allows for proximity to binding region Terminal methyl group increases hydrophobicity

Burimamide

Imidazole Ring Development 

Two tautomers possible, protonation on alternating nitrogens through inductive effects Enhance basicity: addition of electron donating group  Decrease basicity: addition of electron withdrawing group 

Metiamide

Cimetidine (Tagmet®)  

Metiamide is toxic Nitroguanidine and Cyanoguanidine showed similar antagonistic activity 

NO2>CN>OMe>CONH2>Ac>Ph>H

Cimetidine



(anTAGonist ciMETidine)

Rantidine (Zantaz®)  

Replace imidazole ring with furan ring 10x more active than Cimetidine

Rantidine

Famotidine (Pepcid®) 

30x more active than cimetidine

Famotidine

Nizatidine (Axid®)

Nizatidine

Proton Pump 

H+/K+ ATPase   

F-ATPase: in mitocondria and chloroplasts; make ATP with proton gradient V-ATPase: (vacuolar) hydrolyze ATP to generate electrochemical gradient “Proton-Pump” ATPase Animations

Proton Pump Inhibitors 

Exist in inactive form - “prodrugs”   

Readily converted into active form under low pH Become thiol-reactive: sulfenic acid or cyclosulfenamide Intramolecular rearrangment

Inhibitory Mechanism of PPIs

PPIs in clinical use

Rabeprazole

Esomeprazole Mg

Lansoprazole

Pantoprazole

Omeprazole

PPI Kinetic Data

Omeprazole UV spectra

Helicobacter pylori 

Naturally found in stomach of many people Can cause inflammation; leading to membrane erosion



Treated with variety of antibiotics

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

Clarithromycin, Amoxycillan, Tetracyclin

Current Treatment 

Treatment  



H2 anatagonist / PPI Antibiotic against Helicobacter Pylori

Future 

Increase activity, long-lasting effects

Questions?