Anti-Ulcer Agents

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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
• NO2gtCNgtOMegtCONH2gtAcgtPhgtH
• (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
Omeprazole
Pantoprazole
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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
• H2 anatagonist / PPI
• Antibiotic against Helicobacter Pylori
• Future
• Increase activity, long-lasting effects

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Questions?