Download MendeleyDesign, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors.
Potashman, M.H., Bready, J., Coxon, A., Demelfi, T.M., Dipietro, L., Doerr, N., Elbaum, D., Estrada, J., Gallant, P., Germain, J., Gu, Y., Harmange, J.C., Kaufman, S.A., Kendall, R., Kim, J.L., Kumar, G.N., Long, A.M., Neervannan, S., Patel, V.F., Polverino, A., Rose, P., Plas, S.V., Whittington, D., Zanon, R., Zhao, H.(2007) J Med Chem 50: 4351-4373
- PubMed: 17696416
- DOI: https://doi.org/10.1021/jm070034i
- Primary Citation of Related Structures:
2QU5, 2QU6 - PubMed Abstract:
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 and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).
Organizational Affiliation:
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, USA. michelep@amgen.com
