Medicinal Chemistry of GI Drugs - Patient Care 4

Medicinal Chemistry of Gastrointestinal (GI) Drugs

• Topic: Medicinal Chemistry of Gastrointestinal (GI) Drugs
• Speaker: Chengguo Xing, Ph.D.
• Course: Patient Care 4

Learning Objectives

• Recognize the general structures of H2 antagonists (H2 blockers) and proton pump inhibitors (PPI)
• Understand how substitutions affect the antagonistic (inhibitory) efficacy, potency, and selectivity of H2 antagonists
• Know how substitutions affect the mechanism of action of proton pump inhibitors
• Recognize how substitutions contribute to drug-drug interactions and methods to reduce this risk through medicinal chemistry modifications
• Understand the principle behind the development of enantiomeric proton pump inhibitors (racemic switch)

Overview of Lectures

• H2 Receptor Antagonists:
  • Introduction of H1, H2, H3, and H4 receptors
  • Representative drugs for H2 receptors
  • Structural features and key pharmacophores
  • Side effects and drug interactions
  • Case studies
• Proton Pump Inhibitors:
  • Introduction of proton pump
  • Representative drugs
  • Structure requirements and mechanism of action
  • Racemic switch and cases
  • Case studies
• Other GI Drugs:
  • Misoprostol
  • Anti-acids

H1, H2, H3, and H4 Receptors

• Histamine receptors are highly conserved in vertebrates
• Histamine is the endogenous ligand for these receptors
• Histamine has structural similarity to histidine
• Histamine receptors are 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, H4R)
• H1R antagonists are commonly used for allergy treatment and show sedative effects
• H2R antagonists (e.g., cimetidine) are used for treating stomach ulcers
• H3R negatively regulates histamine release, and H4R is involved in immune responses

Histamine Chemistry

• Histamine exists as tautomers (structural isomers that readily interconvert)
• At physiological pH, histamine exists as a mixture of tautomeric cations, primarily monocation (>96%)
• At lower pHs, a larger proportion of the dication exists
• Protonated species are generally considered the biologically active form

Structures of H1, H2, H3, and H4 Receptors

• Diagrams of the receptor structures are presented

Discovery of H2 Antagonists

• H2 antagonists structurally mimic histamine (competitive antagonists)
• Introduction of a methyl group at position 4 may result in a partial agonist
• H2 antagonists display high selectivity for H2 receptors, suggesting that substituent modifications at position 4 might lead to highly selective H2 drug candidates

Representative H2 Antagonists

• Structural features:
  • Competitive antagonists
  • Modifications to the imidazole ring might lead to selectivity toward H2 receptors
  • Four-atom side chains (including sulfur) are associated with higher potency than those with carbon or oxygen atoms
  • Terminal polar non-basic unit (e.g., nitrogen-containing group) are associated with neutral (non-protonated) form at physiological pH Structural representations of histamine, cimetidine, ranitidine, famotidine, and nizatidine are displayed

Cimetidine (Tagamet)

• First H2 antagonist clinically used for GI issues
• Retains the imidazole ring for histamine mimicry
• Inhibits CYP450 metabolic processes, potentially causing drug interactions with other medications (e.g., phenytoin, benzodiazepines, quinidine)
• Less commonly used currently due, potentially, to metabolic processes

Famotidine (Pepcid)

• Significantly more potent than cimetidine
• Minimizes cytochrome P450 enzyme interactions
• Reduced risk of drug-drug interactions compared to cimetidine
• Lower bioavailability due to poor solubility in acidic stomach conditions

Ranitidine

• Replaces imidazole ring with a furan ring, improving tolerability
• Ten times more potent than cimetidine
• Some interaction with cytochrome P450, and it was removed from the market due to potential carcinogen contaminants.

Nizatidine (Tazac or Axid)

• Structurally similar to ranitidine but uses a thiazole ring instead of a furan ring
• Minimal risk of CYP inhibition and drug-drug interactions

Case Study Questions (Pages 17-22)

• Case Study 1:
  • Identify part of famotidine molecule that makes it an H2 antagonist
  • Explain this from molecular structure
• Case Study 2:
  • Identify in/on famotidine the part that increases its potency
• Case Study 3:
  • Choose appropriate alternative for cimetidine (A or B) based on potential for drug interactions with diazepam, explaining the structural rationale for your choice.

Explore the medicinal chemistry behind gastrointestinal drugs, focusing on H2 antagonists and proton pump inhibitors. This quiz covers their structures, mechanisms of action, and impacts of substitutions on efficacy and interactions. Enhance your understanding essential for patient care.