Design, synthesis and biological activity of 6-substituted carbamoyl benzimidazoles as new nonpeptidic angiotensin II AT₁ receptor antagonists.
A series of 6-substituted carbamoyl benzimidazoles were designed and synthesised as new nonpeptidic angiotensin II AT(1) receptor antagonists. The preliminary pharmacological evaluation revealed a nanomolar AT(1) receptor binding affinity for all compounds in the series, and a potent antagonistic activity in an isolated rabbit aortic strip functional assay for compounds 6f, 6g, 6h and 6k was also demonstrated. Furthermore, evaluation in spontaneous hypertensive rats and a preliminary toxicity evaluation showed that compound 6g 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 100081, China.
Jun
J
Zhang
Jin-Liang
JL
Wang
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; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015195:Drug Design; D008958:Models, Molecular; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C575840:N-(2-Phenyl)propyl-1-(2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl-4-methyl-2-n-propyl-1H-benzimidazole-6-carboxamide; D044140:Receptor, Angiotensin, Type 1