GDC-0449——一种有效的刺猬信号通路抑制剂。
GDC-0449-a potent inhibitor of the hedgehog pathway.
作者信息
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 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
机构信息
Genentech, Small Molecule Drug Discovery 1 DNA Way, South San Francisco, CA 94080, United States.
出版信息
Bioorg Med Chem Lett. 2009 Oct 1;19(19):5576-81. doi: 10.1016/j.bmcl.2009.08.049. Epub 2009 Aug 15.
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 12.5mg/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.
对苯并咪唑的多种杂环替代物进行的构效关系（SAR）研究，促成了官能化2-吡啶基酰胺作为刺猬信号通路新型抑制剂的发现。通过对分子的酰胺部分进行修饰，对2-吡啶基酰胺的效力、药代动力学（PK）和类药性质进行了优化，得到了化合物31（GDC-0449）。在完全依赖Hh信号通路生长的髓母细胞瘤同种异体移植小鼠模型中，酰胺31在低至12.5mg/kg每日两次的剂量下即可产生完全的肿瘤消退，该模型目前正处于人体临床试验阶段，最初评估其用于基底细胞癌（BCC）的治疗。
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