title: Design, synthesis and biological evaluation of new 5-nitro benzimidazole derivatives as AT1 antagonists with anti-hypertension activities.
abstract: The design, synthesis, in vitro and in vivo evaluation of 5-nitro benzimidazole with 1,4-disubsituted or 1,5-disubsituted indole derivatives as novel angiotensin II receptor antagonist is outlined. Radioligand binding assays showed that 2-(4-((2-butyl-5-nitro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl)benzoic acid, compound 3, displayed a high affinity for the angiotensin II type 1 receptor with IC50 value of 1.03±0.26nM. The biological evaluation on spontaneously hypertensive rats and renal hypertensive rats showed that 3 could cause significant decrease on MBP in a dose dependent manner, whose maximal response lowered 30mmHg of MBP at 5mg/kg and 41mmHg of MBP at 10mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24h, which is better than Losartan. Taken together 3 could be considered as an effective and durable anti-hypertension drug candidate. These encouraging results are deserved of further investigation towards its use for therapeutic benefit.
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China.
authors.forename: Weibo
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, 2999 North Renmin Road, Shanghai 201620, 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, 2999 North Renmin Road, Shanghai 201620, 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, 2999 North Renmin Road, Shanghai 201620, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, 2999 North Renmin Road, Shanghai 201620, 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, 2999 North Renmin Road, Shanghai 201620, 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, 2999 North Renmin Road, Shanghai 201620, China. Electronic address: zlchen1967@yahoo.com.
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006973:Hypertension / Q000188:drug therapy*; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D044140:Receptor, Angiotensin, Type 1
keywords: 5-Nitro benzimidazole derivatives; AT(1) antagonist; Anti-hypertension; Synthesis