RESUMO
Lead optimization efforts that employed structure base drug design and physicochemical property based optimization leading to the discovery of a novel series of 4-methylpyrido pyrimidinone (MPP) are discussed. Synthesis and profile of 1, a PI3Kα/mTOR dual inhibitor, is highlighted.
Assuntos
Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Piridonas/química , Pirimidinas/química , Pirimidinonas/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Sítios de Ligação , Cristalografia por Raios X , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Piridonas/síntese química , Piridonas/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Pirrolidinas/química , Ratos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismoRESUMO
PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.