title: Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.
abstract: Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Lanqi
authors.initials: L
authors.lastname: Jia
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Simpson
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Zhenrong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Salvacion
authors.initials: S
authors.lastname: Cacatian
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Colin M
authors.initials: CM
authors.lastname: Tice
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Joan
authors.initials: J
authors.lastname: Guo
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Alexey
authors.initials: A
authors.lastname: Ishchenko
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Zhongren
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: McKeever
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bukhtiyarov
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Doe
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Harrison
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Gerard M
authors.initials: GM
authors.lastname: McGeehan
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Dillard
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Baldwin
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Claremon
keywords: Renin; aspartyl protease; hypertension; structure-based drug design