RESUMO
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.
Assuntos
Indazóis/química , Oxazóis/química , Inibidores de Fosfoinositídeo-3 Quinase , Doenças Respiratórias/tratamento farmacológico , Sulfonamidas/química , Administração por Inalação , Animais , Asma/tratamento farmacológico , Feminino , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Indóis , Isoenzimas/antagonistas & inibidores , Masculino , Microssomos/metabolismo , Simulação de Acoplamento Molecular , Ovalbumina/imunologia , Oxazóis/farmacocinética , Oxazóis/farmacologia , Piperazinas , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Coelhos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Células Th2/imunologiaRESUMO
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.
