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


Proton Pump Inhibitors


Tagamet, Zantac, Pepcid, Axid
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

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?