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Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Chong, Pek; Sebahar, Paul; Youngman, Michael; Garrido, Dulce; Zhang, Huichang; Stewart, Eugene L; Nolte, Robert T; Wang, Liping; Ferris, Robert G; Edelstein, Mark; Weaver, Kurt; Mathis, Amanda; Peat, Andrew.
Afiliação
  • Chong P; GlaxoSmithKline Research & Development, 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.
J Med Chem ; 55(23): 10601-9, 2012 Dec 13.
Article em En | MEDLINE | ID: mdl-23137340
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Desenho de Fármacos / Inibidores da Transcriptase Reversa / Transcriptase Reversa do HIV Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Desenho de Fármacos / Inibidores da Transcriptase Reversa / Transcriptase Reversa do HIV Idioma: En Ano de publicação: 2012 Tipo de documento: Article