RESUMEN
The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity together with microsomal stability and only weak activity at the hERG ion channel.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Butanos/síntesis química , Butanos/farmacología , Antagonistas de los Receptores CCR5 , Piperidinas/farmacología , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/química , Butanos/química , Técnicas Químicas Combinatorias , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , VIH/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tropanos/químicaRESUMEN
Optimisation of a series of 4-piperidinyltriazoles led to the identification of compound 28a which showed good whole cell antiviral activity, excellent selectivity over the hERG ion channel and complete oral absorption.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Butanos/síntesis química , Antagonistas de los Receptores CCR5 , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Piperidinas/síntesis química , Animales , Fármacos Anti-VIH/uso terapéutico , Butanos/farmacocinética , Butanos/uso terapéutico , Células CACO-2 , Línea Celular , Perros , Humanos , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Ratas , Receptores CCR5/metabolismo , Estereoisomerismo , Triazoles/síntesis químicaRESUMEN
The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.