Part 2: Structure-activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase

Ryan P Wurz; Liping H Pettus; Bradley Henkle; Lisa Sherman; Matthew Plant; Kent Miner; Helen J McBride; Lu Min Wong; Christiaan J M Saris; Matthew R Lee; Samer Chmait; Christopher Mohr; Faye Hsieh; Andrew S Tasker

doi:10.1016/j.bmcl.2010.01.059

Part 2: Structure-activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1680-4. doi: 10.1016/j.bmcl.2010.01.059. Epub 2010 Jan 21.

Authors

Ryan P Wurz¹, Liping H Pettus, Bradley Henkle, Lisa Sherman, Matthew Plant, Kent Miner, Helen J McBride, Lu Min Wong, Christiaan J M Saris, Matthew R Lee, Samer Chmait, Christopher Mohr, Faye Hsieh, Andrew S Tasker

Affiliation

¹ Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. rwurz@amgen.com

PMID: 20138761
DOI: 10.1016/j.bmcl.2010.01.059

Abstract

A novel class of pyrazolopyridazine p38alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC(50) values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of ca. 0.08mg/kg.

MeSH terms

Administration, Oral
Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / pharmacokinetics
Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / pharmacokinetics
Binding Sites
Cell Line, Tumor
Crystallography, X-Ray
Humans
Interleukin-8
Lipopolysaccharides / toxicity
Male
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacokinetics
Pyridazines / chemical synthesis
Pyridazines / chemistry*
Pyridazines / pharmacokinetics
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Anti-Inflammatory Agents
Benzamides
Interleukin-8
Lipopolysaccharides
Protein Kinase Inhibitors
Pyrazoles
Pyridazines
Tumor Necrosis Factor-alpha
p38 Mitogen-Activated Protein Kinases