RESUMO
A quaternary ammonium betaine 7 is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the αvß6 integrin receptor over the other αv integrins as determined in cell adhesion assays. 7 is prepared by remarkably stereoselective methylation, the origins of which are discussed. The chemical, biological, physicochemical, and pharmacokinetic properties of 7 and its docking into αvß6 are described along with related analogues.
Assuntos
Betaína/farmacologia , Integrinas/antagonistas & inibidores , Pirrolidinas/química , Compostos de Amônio Quaternário/farmacologia , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Betaína/química , Betaína/farmacocinética , Células Cultivadas , Cristalografia por Raios X , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Integrinas/química , Integrinas/metabolismo , Metilação , Modelos Químicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacocinética , Ratos , EstereoisomerismoRESUMO
A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.