title: Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.
abstract: A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.
authors.affiliation: GlaxoSmithKline Research & Development, 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Pek
authors.initials: P
authors.lastname: Chong
authors.forename: Paul
authors.initials: P
authors.lastname: Sebahar
authors.forename: Michael
authors.initials: M
authors.lastname: Youngman
authors.forename: Dulce
authors.initials: D
authors.lastname: Garrido
authors.forename: Huichang
authors.initials: H
authors.lastname: Zhang
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Stewart
authors.forename: Robert T
authors.initials: RT
authors.lastname: Nolte
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ferris
authors.forename: Mark
authors.initials: M
authors.lastname: Edelstein
authors.forename: Kurt
authors.initials: K
authors.lastname: Weaver
authors.forename: Amanda
authors.initials: A
authors.lastname: Mathis
authors.forename: Andrew
authors.initials: A
authors.lastname: Peat
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase