Journal of Medicinal Chemistry 2002-07-04

Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate.

John Regan, Steffen Breitfelder, Pier Cirillo, Thomas Gilmore, Anne G Graham, Eugene Hickey, Bernhard Klaus, Jeffrey Madwed, Monica Moriak, Neil Moss, Chris Pargellis, Sue Pav, Alfred Proto, Alan Swinamer, Liang Tong, Carol Torcellini

Index: J. Med. Chem. 45(14) , 2994-3008, (2002)

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Abstract

We report on a series of N-pyrazole, N'-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5'-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.