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GDC-0449—A potent inhibitor of the hedgehog pathway

2009; Elsevier BV; Volume: 19; Issue: 19 Linguagem: Inglês

10.1016/j.bmcl.2009.08.049

1464-3405

Kirk Robarge, Shirley A. Brunton, Georgette M. Castanedo, Yong Cui, Michael S. Dina, Richard Goldsmith, Stephen E. Gould, Oivin Guichert, Janet L. Gunzner, Jason Halladay, Wei Jia, Cyrus Khojasteh, Michael F. T. Koehler, Karen Kotkow, Hank La, Rebecca Lyn LaLonde, Kevin Lau, Leslie Lee, Derek Marshall, James C. Marsters, Lesley Murray, Changgeng Qian, Lee L. Rubin, Laurent Salphati, Mark Stanley, J. H. A. STIBBARD, Daniel P. Sutherlin, Savita Ubhayaker, Shumei Wang, Susan Wong, Minli Xie,

Ocular Disorders and Treatments

SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.