Med. Chem. II Week SIX
Review and Study Guide

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Drugs Affecting Ion Channels

4. Ion Transport and Diuresis (continued from Week 5)

d. Inhibitors of Na⁺/Cl^--cotransport

• SAR of thiazides
• Physicochemical properties (relative solubility, acidic behavior)
• Structure vs. potency, pharmacokinetic parameters
• Carbonyl bioisosteres of thiazide diuretics

e. Inhibitors of LDT Na⁺/K⁺-exchange process

• Aldosterone antagonists (structure-activity relationships, metabolism)
• Aminopyrazine derivatives

Drugs Affecting the Renin-Angiotensin System (RAS)

1. Biochemical aspects of the RAS (possible sites of pharmacological intervention)

2. Angiotensin (AT) receptor antagonists

a. Peptides (structural design)

b. Nonpeptide AT₁-receptor antagonists

• Structural derivation
• Key structural features (receptor interactions)
• Properties of losartan, valsartan, irbesartan and candesartan

3. Inhibitors of AII biosynthesis (ACE inhibitors)

a. Biochemical function of ACE (AI ----> AII)

b. Structural derivation of active site inhibitors of ACE (interactions with ACE active site)

c. ACEIs

• Structure and ACE inhibition
• Prodrug function
• Steric aspects
• Relative solubility
• Dosage formulation (salt formation)

Drugs Affecting Plasma/Tissue Lipid Concentrations

1. Lipids - physiologic and pharmacologic considerations

2. Pharmacologic approaches to reducing plasma/tissue cholesterol concentrations

a. Stimulation of cholesterol clearance

• Cholesterol metabolism and excretion
• Bile acid sequestrants
  • Structure vs. activity
  • Mechanism of hypocholesterolemic activity

b. Inhibition of cholesterol biosynthesis

• Cholesterol biosynthesis
• Selection of site of inhibition
• HMGCoA Reductase inhibitors
• Structure vs. activity of HMGCoARIs
  • Lactone vs. dihydroxyacid moiety
  • Polycycle structural features
  • Therapeutically-relevant physicochemical properties

Histamine and Drugs Affecting Histamine Function

1. Histamine

a. Structure and physicochemical properties (basicity, tautomerism)

b. Life cycle (biosynthesis, storage and release, metabolic inactivation)

c. Histamine receptors

• Subtypes
• Structure vs. receptor selectivity
• Structure vs. receptor activity (cationization, tautomerism)

2. Histamine H₁-Receptor Antagonists

a. Modification of histamine structure to yield H₁-Receptor Antagonists

b. Physicochemical properties of H₁-Receptor Antagonists

c. First-generation H₁-Receptor Antagonists

d. Second-generation H₁-Receptor Antagonists