Hit to lead optimization of pyrazolo[1,5-a]pyrimidines as B-Raf kinase inhibitors

Ariamala Gopalsamy; Greg Ciszewski; Mengxiao Shi; Dan Berger; Yongbo Hu; Frederick Lee; Larry Feldberg; Eileen Frommer; Steven Kim; Karen Collins; Donald Wojciechowicz; Robert Mallon

doi:10.1016/j.bmcl.2009.10.074

Hit to lead optimization of pyrazolo[1,5-a]pyrimidines as B-Raf kinase inhibitors

Bioorg Med Chem Lett. 2009 Dec 15;19(24):6890-2. doi: 10.1016/j.bmcl.2009.10.074. Epub 2009 Oct 22.

Authors

Ariamala Gopalsamy¹, Greg Ciszewski, Mengxiao Shi, Dan Berger, Yongbo Hu, Frederick Lee, Larry Feldberg, Eileen Frommer, Steven Kim, Karen Collins, Donald Wojciechowicz, Robert Mallon

Affiliation

¹ Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. [email protected]

PMID: 19884006
DOI: 10.1016/j.bmcl.2009.10.074

Abstract

Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases.

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Humans
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Pyrimidines / chemistry*
Pyrimidines / pharmacology

Substances

Antineoplastic Agents
Enzyme Inhibitors
Pyrazoles
Pyrimidines
pyrazolo(1,5-a)pyrimidine
Proto-Oncogene Proteins B-raf