title: N-Phenyl indole derivatives as AT1 antagonists with anti-hypertension activities: Design, synthesis and biological evaluation.
abstract: The design, synthesis, in vitro and in vivo evaluation of 6-substituted benzimidazole with 1, 4-disubsituted or 1, 5-disubsituted indole derivatives as novel angiotensin II receptor antagonists are outlined. Radioligand binding assays showed that several 6-substituted benzimidazole derivatives displayed high affinities binding to the angiotensin II type 1 receptor at the same order of magnitude to telmisartan. The biological evaluation on spontaneously hypertensive rats showed that 2-[4-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole-1-yl]methyl]-1H-indol-1-yl]benzoic acid, 1c, could cause significant decrease on MBP in a dose dependent manner. Its maximal response lowered 53 mmHg of MBP at 5 mg/kg and 64 mmHg of MBP at 10 mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24 h, which was better than both losartan and telmisartan. A study designed to determine acute toxicity showed that 1c had low acute toxicity with no significant changes in the weight and no obvious untoward reactions. The encouraging results make 1c an effective and durable anti-hypertension drug candidate and deserve further investigation for therapeutic application.
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600, China.
authors.forename: Weibo
authors.initials: W
authors.lastname: Zhu
authors.affiliation: State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Bao
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600, China.
authors.forename: He
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Da
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600, China.
authors.forename: Fuming
authors.initials: F
authors.lastname: Li
authors.affiliation: Shanghai Xianhui Pharmaceutical Co., Ltd, Shanghai 200433, China.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600, China. Electronic address: zlchen1967@yahoo.com.
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006973:Hypertension / Q000188:drug therapy*; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D051381:Rats; D011918:Rats, Inbred SHR; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007211:Indoles; D011945:Receptors, Angiotensin
keywords: 6-Substituted benzimidazole; AT(1) antagonists; Acute toxicity; Anti-hypertension; In vitro activity; In vivo activity