RESUMO
We prepared three discreet cohorts of potent non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on the recently reported 3-cyanophenoxypyrazole lead 3. Several of these compounds displayed very promising anti-HIV activity in vitro, safety, pharmacokinetic and pharmaceutical profiles. We describe our analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Nitrilas/química , Pirazóis/química , Inibidores da Transcriptase Reversa/química , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular , Farmacorresistência Viral , Transcriptase Reversa do HIV/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Nitrilas/síntese química , Nitrilas/farmacocinética , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacocinéticaRESUMO
A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability.
