title: Discovery of highly potent renin inhibitors potentially interacting with the S3' subsite of renin.
abstract: To exploit the S3' subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC₅₀ < 3 nM) were identified, among which compounds 38 (IC₅₀ = 0.9 nM) and 39 (IC₅₀ = 0.7 nM) were over 2.5-fold more potent than aliskiren (IC₅₀ = 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 μmol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design.
authors.affiliation: Center for Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Center for Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Wen
authors.affiliation: Department of Physiology, School of Basic Medical Science, Hebei United University, 57 Jianshe South Road, Tangshan 063000, PR China.
authors.forename: Yan-yan
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Center for Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Shi
authors.affiliation: Center for Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Chengzhe
authors.initials: C
authors.lastname: Gao
authors.affiliation: Center for Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Physiology, School of Basic Medical Science, Hebei United University, 57 Jianshe South Road, Tangshan 063000, PR China.
authors.forename: Li-jun
authors.initials: LJ
authors.lastname: Wang
authors.affiliation: Department of Physiology, School of Basic Medical Science, Hebei United University, 57 Jianshe South Road, Tangshan 063000, PR China. Electronic address: ljkyxhljn@163.com.
authors.forename: Xiu-hong
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Center for Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China. Electronic address: hbsun2000@yahoo.com.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D012083:Renin / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D012083:Renin; D000092502:Renin Inhibitors
keywords: Aliskiren; Antihypertension; Renin inhibitors; Structural modification