The discovery of furo[2,3-c]pyridine-based indanone oximes as potent and selective B-Raf inhibitors

Alex J Buckmelter; Li Ren; Ellen R Laird; Bryson Rast; Greg Miknis; Steve Wenglowsky; Stephen Schlachter; Mike Welch; Eugene Tarlton; Jonas Grina; Joseph Lyssikatos; Barbara J Brandhuber; Tony Morales; Nikole Randolph; Guy Vigers; Matthew Martinson; Michele Callejo

doi:10.1016/j.bmcl.2010.12.039

The discovery of furo[2,3-c]pyridine-based indanone oximes as potent and selective B-Raf inhibitors

Bioorg Med Chem Lett. 2011 Feb 15;21(4):1248-52. doi: 10.1016/j.bmcl.2010.12.039. Epub 2010 Dec 10.

Authors

Alex J Buckmelter¹, Li Ren, Ellen R Laird, Bryson Rast, Greg Miknis, Steve Wenglowsky, Stephen Schlachter, Mike Welch, Eugene Tarlton, Jonas Grina, Joseph Lyssikatos, Barbara J Brandhuber, Tony Morales, Nikole Randolph, Guy Vigers, Matthew Martinson, Michele Callejo

Affiliation

¹ Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA.

PMID: 21211972
DOI: 10.1016/j.bmcl.2010.12.039

Abstract

Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf.

MeSH terms

Animals
Binding Sites
Cell Line, Tumor
Computer Simulation
Drug Evaluation, Preclinical
Humans
Indans / chemical synthesis
Indans / chemistry*
Indans / pharmacokinetics
Microsomes, Liver / metabolism
Models, Chemical
Models, Molecular
Oximes / chemical synthesis
Oximes / chemistry*
Oximes / pharmacokinetics
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / metabolism
Pyridines / chemistry*
Rats
Structure-Activity Relationship

Substances

Indans
Oximes
Protein Kinase Inhibitors
Pyridines
indanone oxime
Proto-Oncogene Proteins B-raf
pyridine