Synthesis and biological activity of 2H-quinolizin-2-one based p38alpha MAP kinase inhibitors

Robert M Tynebor; Meng-Hsin Chen; Swaminathan R Natarajan; Edward A O'Neill; James E Thompson; Catherine E Fitzgerald; Stephen J O'Keefe; James B Doherty

doi:10.1016/j.bmcl.2010.03.069

Synthesis and biological activity of 2H-quinolizin-2-one based p38alpha MAP kinase inhibitors

Bioorg Med Chem Lett. 2010 May 1;20(9):2765-9. doi: 10.1016/j.bmcl.2010.03.069. Epub 2010 Mar 21.

Authors

Robert M Tynebor¹, Meng-Hsin Chen, Swaminathan R Natarajan, Edward A O'Neill, James E Thompson, Catherine E Fitzgerald, Stephen J O'Keefe, James B Doherty

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. Robert_tynebor@merck.com

PMID: 20378346
DOI: 10.1016/j.bmcl.2010.03.069

Abstract

The development and synthesis of potent p38alpha MAP kinase inhibitors containing a 2H-quinolizin-2-one platform is described. Evolution of the 2H-quinolizin-2-one series from an early lead to solving off target activity and pharmacokinetic issues is also discussed.

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis*
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / pharmacokinetics
Cell Line
Dogs
Haplorhini
Humans
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Quinolizines / chemical synthesis
Quinolizines / chemistry*
Quinolizines / pharmacokinetics
Rats
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
Protein Kinase Inhibitors
Quinolizines
Tumor Necrosis Factor-alpha
p38 Mitogen-Activated Protein Kinases