Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.

摘要: We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared found to yield nanomolar VEGFR-2 (KDR) with an improved selectivity profile against a panel tyrosine serine/threonine kinases. The inhibitory activity this series was retained at the cellular level. Naphthamides 3, 20, 22 exhibited good pharmacokinetics following oral dosing showed inhibition VEGF-induced angiogenesis in rat corneal model. Once-daily administration for 14 days led 85% established HT29 colon cancer Calu-6 lung xenografts doses 10 20 mg/kg, respectively.