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

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.

• Authors: 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
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 8 Pg. 2634-8 (Apr 15 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20227876 (Publication Type: Journal Article)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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