Nonpeptide Angiotensin II Receptor Antagonists. I. Synthesis and Biological Activity of Pyridine Derivatives

Abstract

Substituted pyridines were synthesized as potential angiotensin II (AII) receptor antagonists. Substitution at the position 2 in the pyridine resulted in potent activity, and the optimal alkyl length was four carbons. The potency further increased with the introduction of a hydroxymethyl group at the position 4. One of the compounds, 2-butyl-6-chloro-4-hydroxymethyl-5-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyridine 9h (KT3-579) is a competitive AII antagonist with a pA₂ value of 9.31, and is about 10 times more potent than Du Pont 753. It was found to be an AT₁ specific antagonist with an IC₅₀ of 3.09nM.