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

• Published in: Journal of medicinal chemistry Vol. 55; no. 6; pp. 2869 - 2881
• Main Authors: Mathieu, Simon, Gradl, Stefan N, Ren, Li, Wen, Zhaoyang, Aliagas, Ignacio, Gunzner-Toste, Janet, Lee, Wendy, Pulk, Rebecca, Zhao, Guiling, Alicke, Bruno, Boggs, Jason W, Buckmelter, Alex J, Choo, Edna F, Dinkel, Victoria, Gloor, Susan L, Gould, Stephen E, Hansen, Joshua D, Hastings, Gregg, Hatzivassiliou, Georgia, Laird, Ellen R, Moreno, David, Ran, Yingqing, Voegtli, Walter C, Wenglowsky, Steve, Grina, Jonas, Rudolph, Joachim
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.03.2012; Amer Chemical Soc
• Subjects: Aminopyridines - chemical synthesis; Aminopyridines - pharmacokinetics; Aminopyridines - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Chemistry, Medicinal; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Life Sciences & Biomedicine; Mice; Models, Molecular; Molecular Structure; Neoplasm Transplantation; Pharmacology & Pharmacy; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Quinazolines - chemical synthesis; Quinazolines - pharmacokinetics; Quinazolines - pharmacology; Rats; Science & Technology; Solubility; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; Transplantation, Heterologous; PATHWAY; DISCOVERY; KINASE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300016v

Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-RafV600E 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-RafV600E mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described.