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.
Pier F Cirillo  1 ,  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
Affiliations
  • 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.