Discovery of novel, potent and low-toxic Angiotension II receptor type 1 (AT1) blockers: Design, synthesis, biological evaluation and molecular docking studies of 6-substituted Aminocarbonyl Benzimidazoles with a chiral

5^th International Conference and Exhibition on Pharmaceutical Regulatory Affairs

August 03-05, 2015 Orlando, USA

Zhi-Ming Zhou, Xiao-Feng Hang, Jun Zhang, Li-Ping Hao, Jin-Liang Wang, Wei-Zhe Xue, Wei-Fa Yu, Fan Fei and Wen-Chang Tao

Beijing Institute of Technology, China

Posters-Accepted Abstracts: Pharmaceut Reg Affairs

Abstract :

Novel AT1 receptor blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step of an investigation devoted to the development of new antihypertensive agents and to the understanding of the pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [125I] Sar1 Ile8-Ang II specifically bound to human AT1 receptor. These radiolig and binding assays revealed nanomolar affinity in several of the compounds under study. The IC50 values of 9 ligands were found to be higher than Losartan. The screening of lowering blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC50=5.0 nM) was equipotent with Losartan, compound 13R (IC50=7.3 nM), 14R (IC50=6.3 nM) and 14S (IC50=3.5 nM) were slightly ahead of Losartan, and the best activity was given by compound 8R (IC50=1.1nM). What was followed, candidate 8R was identified its excellent efficacy of antihypertension and fairly low toxicity based on plasma analysis, toxicology studies and chronically oral test. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT1 receptor model in docking study.

Biography :

Email: zzm@bit.edu.cn