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

• Published in: Bioorganic & medicinal chemistry letters 2010-03, Vol.20 (5), p.1680-1684
• Main Authors: Wurz, Ryan P, Pettus, Liping H, Henkle, Bradley, Sherman, Lisa, Plant, Matthew, Miner, Kent, McBride, Helen J, Wong, Lu Min, Saris, Christiaan J M, Lee, Matthew R, Chmait, Samer, Mohr, Christopher, Hsieh, Faye, Tasker, Andrew S
• Format: Article
• Language: English
• Subjects: 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; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; 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
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2010.01.059

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.