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. Na -Guanylhistamine First partial agonist
First signs of antagonistic activity
Still allows partial conformational change
Guanidine present in A.A. residue arginine
Na -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
NO2>CN>OMe>CONH2>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

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 Esomeprazole Mg Lansoprazole
Pantoprazole
Omeprazole

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

23. Questions?