Design and synthesis of potent pyridazine inhibitors of p38 MAP kinase

Nuria Tamayo; Lillian Liao; Martin Goldberg; David Powers; Yan-Yan Tudor; Violeta Yu; Lu Min Wong; Bradley Henkle; Scot Middleton; Rashid Syed; Timothy Harvey; Graham Jang; Randall Hungate; Celia Dominguez

doi:10.1016/j.bmcl.2005.02.010

Design and synthesis of potent pyridazine inhibitors of p38 MAP kinase

Bioorg Med Chem Lett. 2005 May 2;15(9):2409-13. doi: 10.1016/j.bmcl.2005.02.010.

Authors

Nuria Tamayo¹, Lillian Liao, Martin Goldberg, David Powers, Yan-Yan Tudor, Violeta Yu, Lu Min Wong, Bradley Henkle, Scot Middleton, Rashid Syed, Timothy Harvey, Graham Jang, Randall Hungate, Celia Dominguez

Affiliation

¹ Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. ntamayo@amgen.com

PMID: 15837335
DOI: 10.1016/j.bmcl.2005.02.010

Abstract

Novel potent trisubstituted pyridazine inhibitors of p38 MAP (mitogen activated protein) kinase are described that have activity in both cell-based assays of cytokine release and animal models of rheumatoid arthritis. They demonstrated potent inhibition of LPS-induced TNF-alpha production in mice and exhibited good efficacy in the rat collagen induced arthritis model.

MeSH terms

Binding Sites
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Humans
Indicators and Reagents
Kinetics
Microsomes, Liver / enzymology
Models, Molecular
Molecular Structure
Protein Conformation
Pyridazines / chemical synthesis*
Pyridazines / pharmacology*
Structure-Activity Relationship
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
p38 Mitogen-Activated Protein Kinases / chemistry

Substances

Enzyme Inhibitors
Indicators and Reagents
Pyridazines
p38 Mitogen-Activated Protein Kinases