Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazole derivatives as nonpeptidic angiotensin II AT1 receptor antagonists

• DOI: 10.1016/j.ejmech.2012.01.009
• Publication Date: 2012-01-18T04:18:57Z
• Authors: Jin-Liang Wang; Jun Zhang; Zhi-Ming Zhou; Zhi-Huai Li; Wei-Zhe Xue; Di Xu; Li-Ping Hao; Xiao-Feng Han; Fan Fei; Ting Liu; Ai-Hua Liang
• Keywords: Models, Molecular; 0301 basic medicine; 03 medical and health sciences; Drug Design; Rats, Inbred SHR; Animals; Benzimidazoles; Blood Pressure; Angiotensin II Type 1 Receptor Blockers; Receptor, Angiotensin, Type 1; Rats; 3. Good health

A series of 6-substituted aminocarbonyl benzimidazole derivatives were designed and synthesized as nonpeptidic angiotensin II AT(1) receptor antagonists. The preliminary pharmacological evaluation revealed nanomolar AT(1) receptor binding affinity and good AT(1) receptor selectivity over AT(2) receptor for all compounds of the series, a potent antagonistic activity in isolated rabbit aortic strip functional assay for compounds 6b, 6d and 6i was also demonstrated. Furthermore, evaluation in spontaneous hypertensive rats and a preliminary toxicity evaluation showed that compound 6i is an orally active AT(1) receptor antagonist with low toxicity.