title: Discovery of bioavailable 4,4-disubstituted piperidines as potent ligands of the chemokine receptor 5 and inhibitors of the human immunodeficiency virus-1.
abstract: We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.
authors.affiliation: Infectious Diseases Center for Excellence in Drug Discovery, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. wieslaw.m.kazmierski@gsk.com
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.forename: Christopher
authors.initials: C
authors.lastname: Aquino
authors.forename: Brian A
authors.initials: BA
authors.lastname: Chauder
authors.forename: Felix
authors.initials: F
authors.lastname: Deanda
authors.forename: Robert
authors.initials: R
authors.lastname: Ferris
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Jones-Hertzog
authors.forename: Terrence
authors.initials: T
authors.lastname: Kenakin
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Koble
authors.forename: Christian
authors.initials: C
authors.lastname: Watson
authors.forename: Pat
authors.initials: P
authors.lastname: Wheelan
authors.forename: Hanbiao
authors.initials: H
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Youngman
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects*; D008024:Ligands; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D010880:Piperidines; D019713:Receptors, CCR5; C032727:piperidine