New Nonpeptide Angiotensin II Receptor Antagonists. 1. Synthesis, Biological Properties and Structure-Activity Relationships of 2-Alkyl Benzimidazole Derivatives

Abstract

On the basis of an extension of the literature lead 1, a series of benzimidazoles have been synthesized and shown to be angiotensin II (All) receptor antagonists. The structure-activity relationships of these new antagonists have been explored and the key binding interactions defined. Molecular mechanics calculations were carried out on analogues of imidazole AH antagonists and conformationally restricted analogues were synthesized. The benzimidazole antagonists displaced All in binding studies in vitro with IC50 values in the range 10-5–10-7 M and antagonized the hypertensive effects of All in vivo (rats) following intravenous administration with ED50 values in the range of 5–20 mg/kg. © 1992, American Chemical Society. All rights reserved.