title: Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers, part I: core region.
abstract: Ritonavir (RTV), an HIV-1 protease inhibitor (PI), is also a potent mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) and has been widely prescribed as a pharmacoenhancer. As a boosting agent for marketed PIs, it reduces pill burden, and improves compliance. Removal of the hydroxyl group from RTV reduces, but does not eliminate HIV PI activity and does not affect CYP3A inhibition. Herein we report the discovery of a novel series of CYP3A inhibitors that are devoid of antiviral activity. The synthesis and evaluation of analogs with extensive modifications of the 1,4-diamine core along with the structure activity relationships with respect to anti-HIV activity, CYP3A inhibitory activity, selectivity against other CYP enzymes and the human pregnane X receptor (PXR) will be discussed.
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA. Electronic address: hongtao.liu@gilead.com.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA.
authors.forename: Lianhong
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA.
authors.forename: Hon
authors.initials: H
authors.lastname: Hui
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Vivian
authors.affiliation: Department of Biology, Gilead Sciences, Foster City, CA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Callebaut
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Foster City, CA, USA.
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Murray
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Hong
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Foster City, CA, USA.
authors.forename: Melody S
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Biology, Gilead Sciences, Foster City, CA, USA.
authors.forename: Luong K
authors.initials: LK
authors.lastname: Tsai
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Foster City, CA, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Chau
authors.affiliation: Department of Biology, Gilead Sciences, Foster City, CA, USA.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Stray
authors.affiliation: Department of Structural Chemistry, Gilead Sciences, Foster City, CA, USA.
authors.forename: Carina
authors.initials: C
authors.lastname: Cannizzaro
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA.
authors.forename: You-Chul
authors.initials: YC
authors.lastname: Choi
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Foster City, CA, USA.
authors.forename: Gerry R
authors.initials: GR
authors.lastname: Rhodes
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA.
authors.forename: Manoj C
authors.initials: MC
authors.lastname: Desai
mesh_terms: D065692:Cytochrome P-450 CYP3A Inhibitors; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006678:HIV / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D003959:Diamines; D017320:HIV Protease Inhibitors
keywords: 1,4-Diamines; CYP3A inhibitors; HIV-1 protease inhibitors; Pharmacoenhancer; Selectivity against different CYP enzymes