title: Nonpeptidic angiotensin II AT₁ receptor antagonists derived from 6-substituted aminocarbonyl and acylamino benzimidazoles.
abstract: Both 6-substituted aminocarbonyl and acylamino benzimidazole derivatives were designed and synthesized as nonpeptidic angiotensin II AT₁ receptor antagonists. Compounds 6f, 6g, 11e, 11f, 11g, and 12 showed nanomolar AT₁ receptor binding affinity and high AT₁ receptor selectivity over AT₂ receptor in a preliminary pharmacological evaluation. Among them, the two most active compounds 6f (AT₁ IC₅₀ = 3 nM, AT₂ IC₅₀ > 10,000 nM, PA₂ = 8.51) and 11g (AT₁ IC₅₀ = 0.1 nM, AT₂ IC₅₀ = 149 nM, PA₂ = 8.43) exhibited good antagonistic activity in isolated rabbit aortic strip functional assay. In addition, they were orally active AT₁ receptor antagonists in spontaneous hypertensive rats.
authors.affiliation: R&D Center for Pharmaceuticals, School of Chemical Engineering & The Environment, Beijing Institute of Technology, Beijing 100081, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Jin-Liang
authors.initials: JL
authors.lastname: Wang
authors.forename: Wei-Fa
authors.initials: WF
authors.lastname: Yu
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Zhou
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Tao
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Wang
authors.forename: Wei-Zhe
authors.initials: WZ
authors.lastname: Xue
authors.forename: Di
authors.initials: D
authors.lastname: Xu
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Hao
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Han
authors.forename: Fan
authors.initials: F
authors.lastname: Fei
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Liang
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D044140:Receptor, Angiotensin, Type 1
keywords: Acylamino benzimidazole; Aminoacyl benzimidazole; Angiotensin II AT1 receptor antagonists; Hypertension