Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors

Savithri Ramurthy; Sharadha Subramanian; Mina Aikawa; Payman Amiri; Abran Costales; Jeff Dove; Susan Fong; Johanna M Jansen; Barry Levine; Sylvia Ma; Christopher M McBride; Jonah Michaelian; Teresa Pick; Daniel J Poon; Sandhya Girish; Cynthia M Shafer; Darrin Stuart; Leonard Sung; Paul A Renhowe

doi:10.1021/jm801050k

Design and synthesis of orally bioavailable benzimidazoles as Raf kinase inhibitors

J Med Chem. 2008 Nov 27;51(22):7049-52. doi: 10.1021/jm801050k.

Affiliation

¹ Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608, USA. savithri.ramurthy@novartis.com

PMID: 18942827
DOI: 10.1021/jm801050k

Abstract

A series of arylaminobenzimidazoles was designed and synthesized as Raf kinase inhibitors. Exploration of the structure-activity relationship resulted in compounds that are potent in vitro and show desirable in vivo properties.

MeSH terms

Administration, Oral
Animals
Benzimidazoles / administration & dosage
Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Biological Availability
Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design*
Female
Humans
Mice
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Structure, Tertiary
Stereoisomerism
Structure-Activity Relationship
Xenograft Model Antitumor Assays
raf Kinases / antagonists & inhibitors*
raf Kinases / metabolism

Substances

Benzimidazoles
Protein Kinase Inhibitors
raf Kinases