Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 4, Pages 1176-1180Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.12.094
Keywords
Insulin-like growth factor 1 receptor (IGF-1R); Inhibitors; Tumor growth inhibition (TGI); Cancer
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Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model. (c) 2010 Elsevier Ltd. All rights reserved.
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