Potent and selective aminopyrimidine-based B-Raf inhibitors with favorable physicochemical and pharmacokinetic properties

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.

MeSH terms

  • Aminopyridines / chemical synthesis*
  • Aminopyridines / pharmacokinetics
  • Aminopyridines / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Quinazolines / chemical synthesis
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology
  • Rats
  • Solubility
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology
  • Transplantation, Heterologous


  • Aminopyridines
  • Antineoplastic Agents
  • Quinazolines
  • Thiophenes
  • Proto-Oncogene Proteins B-raf