Discovery and characterization of the N-phenyl-N'-naphthylurea class of p38 kinase inhibitors

Pier F Cirillo; Eugene R Hickey; Neil Moss; Steffen Breitfelder; Raj Betageri; Tazmeen Fadra; Faith Gaenzler; Thomas Gilmore; Daniel R Goldberg; Victor Kamhi; Thomas Kirrane; Rachel R Kroe; Jeffrey Madwed; Monica Moriak; Matthew Netherton; Christopher A Pargellis; Usha R Patel; Kevin C Qian; Rajiv Sharma; Sanxing Sun; Alan Swinamer; Carol Torcellini; Hidenori Takahashi; Michele Tsang; Zhaoming Xiong

doi:10.1016/j.bmcl.2009.03.104

Discovery and characterization of the N-phenyl-N'-naphthylurea class of p38 kinase inhibitors

Bioorg Med Chem Lett. 2009 May 1;19(9):2386-91. doi: 10.1016/j.bmcl.2009.03.104. Epub 2009 Mar 26.

Affiliation

¹ Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceutical, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.

PMID: 19356929
DOI: 10.1016/j.bmcl.2009.03.104

Abstract

An effort aimed at exploring structural diversity in the N-pyrazole-N'-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N'-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-alpha production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency.

MeSH terms

2-Naphthylamine / analogs & derivatives*
2-Naphthylamine / chemistry
Animals
Chemistry, Organic / methods
Chemistry, Pharmaceutical / methods
Crystallography, X-Ray / methods
Drug Design
Inhibitory Concentration 50
Lipopolysaccharides / metabolism
Mice
Models, Chemical
Molecular Structure
Protein Kinase Inhibitors / pharmacology*
Tumor Necrosis Factor-alpha / metabolism
Urea / analogs & derivatives*
Urea / chemistry
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

Lipopolysaccharides
Protein Kinase Inhibitors
Tumor Necrosis Factor-alpha
di-2-naphthylurea
Urea
2-Naphthylamine
p38 Mitogen-Activated Protein Kinases