2. Academic Validation
  3. Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy

Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy

  • Bioorg Med Chem Lett. 2011 Feb 15;21(4):1176-80. doi: 10.1016/j.bmcl.2010.12.094.
Meizhong Jin 1,  Andrew Kleinberg,  Andy Cooke,  Prafulla C Gokhale,  Kenneth Foreman,  Hanqing Dong,  Kam W Siu,  Mark A Bittner,  Kristen M Mulvihill,  Yan Yao,  Darla Landfair,  Matthew O'Connor,  Gilda Mak,  Jonathan A Pachter,  Robert Wild,  Maryland Rosenfeld-Franklin,  Qunsheng Ji,  Mark J Mulvihill
Affiliations

Affiliation

  • 1 (OSI) Oncology, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA. mjin@osip.com
PMID: 21251824 DOI: 10.1016/j.bmcl.2010.12.094
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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