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 4-methylhistamine
Conformation I Conformation II
Na -Guanylhistamine

 First partial agonist

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

Na -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

 Clarithromycin, Amoxycillan, Tetracyclin
Current Treatment

 Treatment
 H2 anatagonist / PPI
 Antibiotic against Helicobacter Pylori

 Future
 Increase activity, long-lasting effects
Questions?