Identification of SD-0006, a potent diaryl pyrazole inhibitor of p38 MAP kinase

John K Walker; Shaun R Selness; Rajesh V Devraj; Michael E Hepperle; Win Naing; Huey Shieh; Ravi Kurambail; Syaulan Yang; Daniel L Flynn; Alan G Benson; Dean M Messing; Tom Dice; Tina Kim; R J Lindmark; Joseph B Monahan; Joseph Portanova

doi:10.1016/j.bmcl.2010.02.047

Identification of SD-0006, a potent diaryl pyrazole inhibitor of p38 MAP kinase

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2634-8. doi: 10.1016/j.bmcl.2010.02.047. Epub 2010 Feb 14.

Authors

John K Walker¹, Shaun R Selness, Rajesh V Devraj, Michael E Hepperle, Win Naing, Huey Shieh, Ravi Kurambail, Syaulan Yang, Daniel L Flynn, Alan G Benson, Dean M Messing, Tom Dice, Tina Kim, R J Lindmark, Joseph B Monahan, Joseph Portanova

Affiliation

¹ Pfizer Global Research and Development, St. Louis, MO 63017, USA. jkwalker24@sbcglobal.net

PMID: 20227876
DOI: 10.1016/j.bmcl.2010.02.047

Abstract

Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.

MeSH terms

Animals
Catalytic Domain
Humans
Models, Molecular
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / pharmacology*
Pyrimidines / pharmacology*
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
SD 0006
p38 Mitogen-Activated Protein Kinases