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 Tagamet, Zantac, Pepcid, Axid Proton Pump Inhibitors 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

Na -Guanylhistamine First partial agonist First signs of antagonistic activity Still allows partial conformational change Guanidine present in A.A. residue arginine Na -Guanylhistamine

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 (anTAGonist ciMETidine) 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 Clarithromycin, Amoxycillan, Tetracyclin

Current Treatment Treatment Future H2 anatagonist / PPI Antibiotic against Helicobacter Pylori Future Increase activity, long-lasting effects

Questions?