title: Synthesis and evaluation of novel angiotensin II receptor 1 antagonists as anti-hypertension drugs.
abstract: Three new angiotensin II receptor 1 antagonists, 1, 2 and 3 were designed, synthesized and evaluated. The AT1 receptor-binding assays in vitro showed that all the synthesized compounds had nanomolar affinity for the AT1 receptor. From which compound 3 was found to be the most potent ligands with an IC50 value of 2.67±0.23 nM. Biological evaluation in vivo revealed that all the compounds could cause significant decrease on MBP in a dose dependent manner in spontaneously hypertensive rats, and compound 3 especially showed an efficient and long-lasting effect in reducing blood pressure, whose maximal response lowered 41 mmHg of MBP at 10mg/kg and 62 mmHg at 15 mg/kg after oral administration, the significant anti-hypertensive effect lasted beyond 12 h, which is better than the reference compound losartan. The pharmacokinetic experiments showed that compound 3 could be absorbed efficiently and metabolized smoothly both in blood and in tissues in Wistar rats. The acute toxicity assay suggested that it has low toxicity with the LD50 value of 2974.35 mg/kg. These results demonstrate that compound 3 is a potent angiotensin AT1 receptor antagonist which could be considered as a novel anti-hypertension candidate and deserved for further investigation.
authors.affiliation: State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, PR 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, 2999 North Renmin Road, Shanghai 201620, PR 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, PR China.
authors.forename: Ruijing
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, 2999 North Renmin Road, Shanghai 201620, PR China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Wen
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, 2999 North Renmin Road, Shanghai 201620, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Ningbo Dongmi Pharmaceutical Co., Ltd, Ningbo 315899, Zhejiang, PR China.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Shanghai Xianhui Pharmaceutical Co., Ltd, Shanghai 200433, PR China.
authors.forename: Hesheng
authors.initials: H
authors.lastname: Tang
authors.affiliation: State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, PR China; Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, 2999 North Renmin Road, Shanghai 201620, PR China. Electronic address: zlchen1967@qq.com.
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents
keywords: AT(1) receptor antagonist; Angiotensin II; Anti-hypertension; Hypertension