Discovery of an Orally Efficacious Imidazo[5,1-f][1,2,4]triazine Dual Inhibitor of IGF-1R and IR
ACS Medicinal Chemistry Letters2010Vol. 1(9), pp. 510–515
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Meizhong Jin, Prafulla C. Gokhale, Andy Cooke, Kenneth W. Foreman, Elizabeth Buck, Earl W. May, Lixin Feng, Mark Bittner, Mridula Kadalbajoo, Darla Landfair, Kam Siu, Kathryn M. Stolz, Douglas S. Werner, Radoslaw S. Laufer, An‐Hu Li, Hanqing Dong, Arno G. Steinig, Andrew Kleinberg, Yan Yao, Jonathan A. Pachter, Robert A. Wild, Mark J. Mulvihill
Abstract
This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacological activity of compound 9b, a potent, selective, well-tolerated, and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in tumor xenograft models, is discussed.
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