RESUMO
Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Pirróis/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Triazinas/síntese química , Administração Oral , Quinase do Linfoma Anaplásico , Compostos de Anilina/farmacocinética , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Técnicas In Vitro , Camundongos , Camundongos SCID , Microssomos Hepáticos/metabolismo , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.