Potent and Selective Aminopyrimidine-Based B-Raf Inhibitors with Favorable Physicochemical and Pharmacokinetic Properties

详细信息    查看全文

• 作者：Simon Mathieu ; Stefan N. Gradl ; Li Ren ; Zhaoyang Wen ; Ignacio Aliagas ; Janet Gunzner-Toste ; Wendy Lee ; Rebecca Pulk ; Guiling Zhao ; Bruno Alicke ; Jason W. Boggs ; Alex J. Buckmelter ; Edna F. Choo ; Victoria Dinkel ; Susan L. Gloor ; Stephen E. Gould ; Joshua D. Hansen ; Gregg Hastings ; Georgia Hatzivassiliou ; Ellen R. Laird ; David Moreno ; Yingqing Ran ; Walter C. Voegtli ; Steve Wenglowsky ; Jonas Grina ; Joachim Rudolph
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 22, 2012
• 年：2012
• 卷：55
• 期：6
• 页码：2869-2881
• 全文大小：483K
• 年卷期：v.55,no.6(March 22, 2012)
• ISSN：1520-4804

文摘

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.