Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors
文摘
Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers.Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVECcellular proliferation assays. In this report we describe the synthesis and structure-activity relationship ofa series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observedat 100 mg/kg) and the rat corneal angiogenesis model (ED50 = 16.3 mg/kg).