RESUMEN
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
Asunto(s)
Indazoles/química , Oxazoles/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Enfermedades Respiratorias/tratamiento farmacológico , Sulfonamidas/química , Administración por Inhalación , Animales , Asma/tratamiento farmacológico , Femenino , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Indoles , Isoenzimas/antagonistas & inhibidores , Masculino , Microsomas/metabolismo , Simulación del Acoplamiento Molecular , Ovalbúmina/inmunología , Oxazoles/farmacocinética , Oxazoles/farmacología , Piperazinas , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Conejos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Células Th2/inmunologíaRESUMEN
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.