Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
J Med Chem. 2012 Mar 22;55(6):2869-81. doi: 10.1021/jm300016v. Epub 2012 Feb 29.
Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-Raf(V600E) mutant melanoma. Pyrazolopyridine-type B-Raf inhibitors previously described by the authors are potent and selective but exhibit low solubility requiring the use of amorphous dispersion-based formulation for achieving efficacious drug exposures. Through structure-based design, we discovered a new class of highly potent aminopyrimidine-based B-Raf inhibitors with improved solubility and pharmacokinetic profiles. The hinge binding moiety possesses a basic center imparting high solubility at gastric pH, addressing the dissolution limitation observed with our previous series. In our search for an optimal linker-hinge binding moiety system, amide-linked thieno[3,2-d]pyrimidine analogues 32 and 35 (G945), molecules with desirable physicochemical properties, emerged as lead compounds with strong efficacy in a B-Raf(V600E) mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described.
最近的临床数据为选择性 B-Raf 抑制剂治疗 B-Raf(V600E)突变型黑色素瘤提供了概念验证。作者之前描述的吡唑并吡啶型 B-Raf 抑制剂具有很强的选择性，但溶解度低，需要使用无定形分散制剂来实现有效的药物暴露。通过基于结构的设计，我们发现了一类新的高活性的基于氨基嘧啶的 B-Raf 抑制剂，具有改善的溶解度和药代动力学特征。铰链结合部分具有碱性中心，在胃 pH 值下具有高溶解度，解决了我们之前系列中观察到的溶解限制问题。在我们寻找最佳的连接子-铰链结合部分系统的过程中，酰胺连接的噻吩并[3,2-d]嘧啶类似物 32 和 35（G945）作为先导化合物出现，具有理想的物理化学性质，在 B-Raf(V600E)突变型小鼠异种移植模型中具有很强的疗效。将描述合成、SAR、先导化合物的选择以及动物研究中关键化合物的评估。
