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J Med Chem
; 58(20): 8154-65, 2015 Oct 22.
Artigo
em Inglês
| MEDLINE
| ID: mdl-26397965
RESUMO
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Animais , Área Sob a Curva , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Integrase de HIV/efeitos dos fármacos , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacocinética , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Modelos Moleculares , Pró-Fármacos , Piridonas/farmacocinética , Ratos
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