Enhanced selectivity profile of pyrazole-urea based DFG-out p38alpha inhibitors

Hu Liu; Cyrille Kuhn; Frederic Feru; Suzanne L Jacques; Gayatri D Deshmukh; Ping Ye; Glen R Rennie; Theresa Johnson; Steven Kazmirski; Simon Low; Rocco Coli; Yuan-hua Ding; Alan C Cheng; Haile Tecle; Jessie M English; Robert Stanton; Joe C Wu

doi:10.1016/j.bmcl.2010.06.073

Enhanced selectivity profile of pyrazole-urea based DFG-out p38alpha inhibitors

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4885-91. doi: 10.1016/j.bmcl.2010.06.073. Epub 2010 Jun 17.

Authors

Hu Liu¹, Cyrille Kuhn, Frederic Feru, Suzanne L Jacques, Gayatri D Deshmukh, Ping Ye, Glen R Rennie, Theresa Johnson, Steven Kazmirski, Simon Low, Rocco Coli, Yuan-hua Ding, Alan C Cheng, Haile Tecle, Jessie M English, Robert Stanton, Joe C Wu

Affiliation

¹ Department of Chemistry, Cambridge South Laboratories, Pfizer Inc., 620 Memorial Drive, Cambridge, MA 02139, USA. hu.liu@pfizer.com

PMID: 20620059
DOI: 10.1016/j.bmcl.2010.06.073

Abstract

By targeting an extended region of the conventional 'DFG-out' pocket of p38alpha, while minimizing interactions with the specificity pocket and eliminating interactions with the adenine binding site, we are able to design and synthesize a number of pyrazole-urea based DFG-out p38alpha inhibitors with good potencies, and excellent selectivity.

MeSH terms

Adenine / metabolism
Amino Acid Motifs
Amino Acid Sequence
Binding Sites
Humans
Microsomes / metabolism
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 14 / metabolism*
Phenylurea Compounds / chemical synthesis
Phenylurea Compounds / chemistry*
Phenylurea Compounds / pharmacology
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Structure-Activity Relationship

Substances

Phenylurea Compounds
Protein Kinase Inhibitors
Pyrazoles
Mitogen-Activated Protein Kinase 14
Adenine