RESUMEN
As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC50 = 9.0 nM), human microsomal metabolic stability (t1/2 = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development.
Asunto(s)
Antineoplásicos/uso terapéutico , Glioblastoma/tratamiento farmacológico , Naftiridinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Quinazolinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Femenino , Humanos , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Naftiridinas/síntesis química , Naftiridinas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Quinazolinas/síntesis química , Quinazolinas/metabolismo , Ratas , Relación Estructura-Actividad , Termodinámica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A potent and novel MET inhibitor, 5-((4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)amino)-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-ones (8), was designed and synthesized via a scaffold-hopping strategy of a 2,7-naphthyridinone MET kinase inhibitor 7. Lead compound 8 had good potency (IC50 of 9.8â¯nM), but unfavorable pharmacokinetic profiles (Fâ¯=â¯12%, CLâ¯=â¯5.0â¯L/h/kg). Systematic structural optimization of compound 8 resulted in 9g (MET, IC50â¯=â¯of 9.8â¯nM) with a comparable MET potency to that of compound 2 and a favorable pharmacokinetic profile (Fâ¯=â¯63%, CLâ¯=â¯0.12â¯L/h/kg). Further study of the derivatization of N(1) amine group of 9g led to the discovery of 23a with good MET potency (IC50 of 7.1â¯nM), promising VEGFR-2 selectivity (3226-fold), and a markedly drug-likeness improvement (Fâ¯=â¯57.7%, CLâ¯=â¯0.02â¯L/h/kg). The excellent VEGFR-2 selectivity and favorable drug-likeness of 23g suggest that the 1,6-naphthyridine moiety could be used as a new scaffold for kinase inhibitor discovery.