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, 21 (4), 1176-80

Potent and Selective Cyclohexyl-Derived Imidazopyrazine Insulin-Like Growth Factor 1 Receptor Inhibitors With in Vivo Efficacy

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Potent and Selective Cyclohexyl-Derived Imidazopyrazine Insulin-Like Growth Factor 1 Receptor Inhibitors With in Vivo Efficacy

Meizhong Jin et al. Bioorg Med Chem Lett.

Abstract

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.

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