Potent and Selective Aminopyrimidine-Based B-Raf Inhibitors with Favorable Physicochemical and Pharmacokinetic Properties
| Autor: | Janet Gunzner-Toste, Edna F. Choo, Bruno Alicke, Stephen E. Gould, Rebecca Pulk, Ellen R. Laird, Zhaoyang Wen, Li Ren, Jonas Grina, Jason Boggs, David A. Moreno, Joachim Rudolph, Alexandre J. Buckmelter, Simon Mathieu, Guiling Zhao, Stefan Gradl, Walter C. Voegtli, Yingqing Ran, Ignacio Aliagas, Joshua D. Hansen, Georgia Hatzivassiliou, Wendy Lee, Victoria Dinkel, Steve Wenglowsky, Gregg Hastings, Susan L. Gloor |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Proto-Oncogene Proteins B-raf Drug Stereochemistry media_common.quotation_subject Transplantation Heterologous Mutant Aminopyridines Antineoplastic Agents Thiophenes Crystallography X-Ray Mice Structure-Activity Relationship Pyrimidine analogue Pharmacokinetics Mouse xenograft Cell Line Tumor Drug Discovery Animals Moiety Solubility media_common Molecular Structure Chemistry Rats Gastric ph Quinazolines Molecular Medicine Drug Screening Assays Antitumor Neoplasm Transplantation |
| Zdroj: | Journal of Medicinal Chemistry. 55:2869-2881 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm300016v |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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