Discovery of novel, potent and low-toxicity angiotensin II receptor type 1 (AT1) blockers: Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazoles with a chiral center.

Abstract Novel angiotensin II receptor type 1 (AT 1 ) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [ 125 I] Sar 1 Ile 8 -Ang II, which was specifically bound to human AT 1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC 50 values of nine ligands were higher than those of Losartan. The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC 50  = 5.0 nM) was equipotent with Losartan, whereas compounds 13R (IC 50  = 7.3 nM), 14R (IC 50  = 6.3 nM), and 14S (IC 50  = 3.5 nM) were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R (IC 50  = 1.1 nM). Candidate 8R was identified for its excellent efficacy in antihypertension and fairly low toxicity based on plasma analyses, toxicology studies, and chronic oral tests. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT 1 receptor model in docking study.