Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazole derivatives as nonpeptidic angiotensin II AT1 receptor antagonists.
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.
R&D Center for Pharmaceuticals, School of Chemical Engineering & the Environment, Beijing Institute of Technology, Beijing, China.
Jin-Liang
JL
Wang
Jun
J
Zhang
Zhi-Ming
ZM
Zhou
Zhi-Huai
ZH
Li
Wei-Zhe
WZ
Xue
Di
D
Xu
Li-Ping
LP
Hao
Xiao-Feng
XF
Han
Fan
F
Fei
Ting
T
Liu
Ai-Hua
AH
Liang
D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D015195:Drug Design; D008958:Models, Molecular; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D044140:Receptor, Angiotensin, Type 1