title: Biphenyl/diphenyl ether renin inhibitors: filling the S1 pocket of renin via the S3 pocket.
abstract: Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.
authors: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA. jyuan@vitaerx.com
authors: Jing
authors: J
authors: Yuan
authors: Robert D
authors: RD
authors: Simpson
authors: Wei
authors: W
authors: Zhao
authors: Colin M
authors: CM
authors: Tice
authors: Zhenrong
authors: Z
authors: Xu
authors: Salvacion
authors: S
authors: Cacatian
authors: Lanqi
authors: L
authors: Jia
authors: Patrick T
authors: PT
authors: Flaherty
authors: Joan
authors: J
authors: Guo
authors: Alexey
authors: A
authors: Ishchenko
authors: Zhongren
authors: Z
authors: Wu
authors: Brian M
authors: BM
authors: McKeever
authors: Boyd B
authors: BB
authors: Scott
authors: Yuri
authors: Y
authors: Bukhtiyarov
authors: Jennifer
authors: J
authors: Berbaum
authors: Reshma
authors: R
authors: Panemangalore
authors: Ross
authors: R
authors: Bentley
authors: Christopher P
authors: CP
authors: Doe
authors: Richard K
authors: RK
authors: Harrison
authors: Gerard M
authors: GM
authors: McGeehan
authors: Suresh B
authors: SB
authors: Singh
authors: Lawrence W
authors: LW
authors: Dillard
authors: John J
authors: JJ
authors: Baldwin
authors: David A
authors: DA
authors: Claremon
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A / Q000097:blood; D065692:Cytochrome P-450 CYP3A Inhibitors; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008958:Models, Molecular; D008968:Molecular Conformation; D010647:Phenyl Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D055647:Rats, Transgenic; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000959:Antihypertensive Agents; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D010647:Phenyl Ethers; D011994:Recombinant Proteins; D000092502:Renin Inhibitors; C510163:CYP3A4 protein, human