RESUMEN
The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.
Asunto(s)
Inhibidores Enzimáticos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Piridinas , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Animales , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Furanos/síntesis química , Furanos/química , Furanos/farmacología , Humanos , Concentración 50 Inhibidora , Quinasas Quinasa Quinasa PAM/metabolismo , Ratones , Estructura Molecular , Neoplasias/tratamiento farmacológico , Fosfotransferasas/química , Fosfotransferasas/metabolismo , Piridinas/síntesis química , Piridinas/farmacocinética , Piridinas/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.