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Optimization of alpha-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric
Antonio Garrido Montalban1, Erik Boman, Chau-Dung Chang
1Drug Discovery, Kémia, Inc., 5871 Oberlin Drive, Suite 100, San Diego, CA 92121, USA. catalaba@hotmail.com
Abstract:
We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.
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