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

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Presentation on theme: "Anti-Ulcer Agents Michael Alwan November 11, 2004 Medicinal Chemistry. Southern Methodist Univ."— Presentation transcript:

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

2 What is Peptic Ulcer? An Ulcer is …  Localized erosion in stomach or duodenum

3 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

4 Rational Approach to Drug Design Histamine 2 Receptors  Tagamet, Zantac, Pepcid, Axid Proton Pump Inhibitors  Protonix, Prilosec, Prevacid, Aciphex, Nexium Antibiotics  Clarithromycin, Amoxycillan, Tetracyclin

5 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 …

6 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 …

7 4-methylhistamine Not an antagonist, but highly H2 selective  Conformational isomers show preferential binding 4-methylhistamine Conformation I 4-methylhistamine Conformation II

8 N  -Guanylhistamine First partial agonist  First signs of antagonistic activity  Still allows partial conformational change  Guanidine present in A.A. residue arginine N  -Guanylhistamine

9 Carbon chain lengthened Two-carbon chain, speculation of a carboxylate binding region Three-carbon chain, speculation of different binding region

10 Burimamide Enhanced antagonist activity  Longer chain allows for proximity to binding region  Terminal methyl group increases hydrophobicity Burimamide

11 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

12 Cimetidine (Tagmet ® ) Metiamide is toxic Nitroguanidine and Cyanoguanidine showed similar antagonistic activity  NO 2 >CN>OMe>CONH 2 >Ac>Ph>H  (anTAGonist ciMETidine) Cimetidine

13 Rantidine (Zantaz ® ) Replace imidazole ring with furan ring 10x more active than Cimetidine Rantidine

14 Famotidine (Pepcid ® ) 30x more active than cimetidine Famotidine

15 Nizatidine (Axid ® ) Nizatidine

16 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 ATPase Animations

17 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

18 Inhibitory Mechanism of PPIs

19 PPIs in clinical use Rabeprazole OmeprazolePantoprazole Lansoprazole Esomeprazole Mg

20 PPI Kinetic Data Omeprazole UV spectra

21 Helicobacter pylori Naturally found in stomach of many people Can cause inflammation; leading to membrane erosion Treated with variety of antibiotics  Clarithromycin, Amoxycillan, Tetracyclin

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

23 Questions?


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