RESUMO
Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.
Assuntos
Desenho de Fármacos , Indóis/síntese química , Piperidinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Citocromo P-450 CYP3A/metabolismo , Feminino , Meia-Vida , Humanos , Indóis/farmacocinética , Indóis/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Neoplasias/tratamento farmacológico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Ratos , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.
Assuntos
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Animais , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Haplorrinos , Humanos , Camundongos , Microssomos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Pirazóis/química , Piridinas/químicaRESUMO
The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.