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Anti-Ulcer Agents Michael Alwan November 11, 2004
Medicinal Chemistry. Southern Methodist Univ.
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What is Peptic Ulcer? An Ulcer is …
Localized erosion in stomach or duodenum
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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
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Rational Approach to Drug Design
Histamine 2 Receptors Tagamet, Zantac, Pepcid, Axid Proton Pump Inhibitors Protonix, Prilosec, Prevacid, Aciphex, Nexium Antibiotics Clarithromycin, Amoxycillan, Tetracyclin
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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 …
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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 …
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4-methylhistamine Not an antagonist, but highly H2 selective
Conformational isomers show preferential binding 4-methylhistamine Conformation I 4-methylhistamine Conformation II
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Na -Guanylhistamine First partial agonist
First signs of antagonistic activity Still allows partial conformational change Guanidine present in A.A. residue arginine Na -Guanylhistamine
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Carbon chain lengthened
Two-carbon chain, speculation of a carboxylate binding region Three-carbon chain, speculation of different binding region
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Burimamide Enhanced antagonist activity
Longer chain allows for proximity to binding region Terminal methyl group increases hydrophobicity Burimamide
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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
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Cimetidine (Tagmet®) Metiamide is toxic
Nitroguanidine and Cyanoguanidine showed similar antagonistic activity NO2>CN>OMe>CONH2>Ac>Ph>H (anTAGonist ciMETidine) Cimetidine
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Rantidine (Zantaz®) Replace imidazole ring with furan ring
10x more active than Cimetidine Rantidine
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Famotidine (Pepcid®) 30x more active than cimetidine Famotidine
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Nizatidine (Axid®) Nizatidine
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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
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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
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Inhibitory Mechanism of PPIs
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PPIs in clinical use Rabeprazole Esomeprazole Mg Lansoprazole
Pantoprazole Omeprazole
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PPI Kinetic Data Omeprazole UV spectra
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Helicobacter pylori Naturally found in stomach of many people
Can cause inflammation; leading to membrane erosion Treated with variety of antibiotics Clarithromycin, Amoxycillan, Tetracyclin
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Current Treatment Treatment Future H2 anatagonist / PPI
Antibiotic against Helicobacter Pylori Future Increase activity, long-lasting effects
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Questions?
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