5-amino-pyrazoles as potent and selective p38α inhibitors

Jagabandhu Das; Robert V Moquin; Alaric J Dyckman; Tianle Li; Sidney Pitt; Rosemary Zhang; Ding Ren Shen; Kim W McIntyre; Kathleen Gillooly; Arthur M Doweyko; John A Newitt; John S Sack; Hongjian Zhang; Susan E Kiefer; Kevin Kish; Murray McKinnon; Joel C Barrish; John H Dodd; Gary L Schieven; Katerina Leftheris

doi:10.1016/j.bmcl.2010.10.034

5-amino-pyrazoles as potent and selective p38α inhibitors

Bioorg Med Chem Lett. 2010 Dec 1;20(23):6886-9. doi: 10.1016/j.bmcl.2010.10.034. Epub 2010 Oct 13.

Affiliation

¹ Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, USA. jagabandhu.das@bms.com

PMID: 21035336
DOI: 10.1016/j.bmcl.2010.10.034

Abstract

The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.

MeSH terms

Animals
Crystallography, X-Ray
Mice
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 14 / chemistry*
Protein Binding
Protein Conformation
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / biosynthesis

Substances

Protein Kinase Inhibitors
Pyrazoles
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinase 14