GDC-0449—a potent inhibitor of the hedgehog pathway

…, R Goldsmith, SE Gould, O Guichert, JL Gunzner…

文献索引：Robarge, Kirk D.; Brunton, Shirley A.; Castanedo, Georgette M.; Cui, Yong; Dina, Michael S.; Goldsmith, Richard; Gould, Stephen E.; Guichert, Oivin; Gunzner, Janet L.; Halladay, Jason; Jia, Wei; Khojasteh, Cyrus; Koehler, Michael F.T.; Kotkow, Karen; La, Hank; LaLonde, Rebecca L.; Lau, Kevin; Lee, Leslie; Marshall, Derek; Marsters Jr., James C.; Murray, Lesley J.; Qian, Changgeng; Rubin, Lee L.; Salphati, Laurent; Stanley, Mark S.; Stibbard, John H.A.; Sutherlin, Daniel P.; Ubhayaker, Savita; Wang, Shumei; Wong, Susan; Xie, Minli Bioorganic and Medicinal Chemistry Letters, 2009 , vol. 19, # 19 p. 5576 - 5581

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被引用次数: 229

摘要

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 ...