title: Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers. Part II: P2/P3 region and discovery of cobicistat (GS-9350).
abstract: The HIV protease inhibitor (PI) ritonavir (RTV) has been widely used as a pharmacoenhancer for other PIs, which are substrates of cytochrome P450 3A (CYP3A). However the potent anti-HIV activity of ritonavir may limit its use as a pharmacoenhancer with other classes of anti-HIV agents. Ritonavir is also associated with limitations such as poor physicochemical properties. To address these issues a series of compounds with replacements at the P2 and/or P3 region was designed and evaluated as novel CYP3A inhibitors. Through these efforts, a potent and selective inhibitor of CYP3A, GS-9350 (cobicistat) with improved physiochemical properties was discovered.
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA. Electronic address: lianhong.xu@gilead.com.
authors.forename: Lianhong
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Hong
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Vivian
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Murray
authors.affiliation: Department of Biology, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Callebaut
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: You-Chul
authors.initials: YC
authors.lastname: Choi
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Melody S
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chau
authors.affiliation: Department of Biology, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Luong K
authors.initials: LK
authors.lastname: Tsai
authors.affiliation: Department of Biology, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Stray
authors.affiliation: Department of Formulation, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Strickley
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Structural Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Swami
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Gerry R
authors.initials: GR
authors.lastname: Rhodes
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
authors.forename: Manoj C
authors.initials: MC
authors.lastname: Desai
mesh_terms: D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology; D000069547:Cobicistat; D065692:Cytochrome P-450 CYP3A Inhibitors; D003959:Diamines / Q000737:chemistry* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002219:Carbamates; D065692:Cytochrome P-450 CYP3A Inhibitors; D003959:Diamines; D013844:Thiazoles; D000069547:Cobicistat
keywords: 1,4-Diamines; CYP3A inhibitors; Pharmacoenhancer; Selectivity against different CYP enzymes