4-Quinazolinyloxy-diaryl ureas as novel BRAFV600E inhibitors

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5342-6. doi: 10.1016/j.bmcl.2011.07.019. Epub 2011 Jul 14.

Abstract

Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Mice
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tissue Distribution
  • Urea / analogs & derivatives
  • Urea / chemistry
  • Urea / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Protein Kinase Inhibitors
  • Quinazolines
  • Urea
  • Proto-Oncogene Proteins B-raf