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.

Keywords

ChemistryPharmacophorePyrazoleBinding siteHydrogen bondLead compoundBinding pocketStereochemistryProtein kinase APlasma protein bindingKinaseCombinatorial chemistryBiochemistryMoleculeIn vitro

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Year
2002
Type
article
Volume
45
Issue
14
Pages
2994-3008
Citations
348
Access
Closed

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John R. Regan, Steffen Breitfelder, Pier F. Cirillo et al. (2002). Pyrazole Urea-Based Inhibitors of p38 MAP Kinase:  From Lead Compound to Clinical Candidate. Journal of Medicinal Chemistry , 45 (14) , 2994-3008. https://doi.org/10.1021/jm020057r

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DOI
10.1021/jm020057r