Optimization of α-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site

Autor:	Zhijun Wang, Erik Boman, Jan Urban, Jeff Kucharski, Hiroshi Nakanishi, Jan Lundström, Nancy G. J. Delaet, Justin T. Ernst, Eddine Saiah, Christopher Lum, Eric Erb, Antonio Garrido Montalban, Susana Conde Ceide, Russell Dahl, Linda Kessler, Stephen E. Miller, Christopher J. Larson, Chau-Dung Chang, Edward Roberts, Jeffrey Kahl, Robert K. P. Sullivan, Andrew Gibbs, David Dalesandro
Rok vydání:	2010
Předmět:	Stereochemistry Clinical Biochemistry Allosteric regulation Administration Oral Pharmaceutical Science Plasma protein binding p38 Mitogen-Activated Protein Kinases Biochemistry Cell Line Structure-Activity Relationship In vivo Drug Discovery Animals Humans Structure–activity relationship Computer Simulation Binding site Protein Kinase Inhibitors Molecular Biology ADME Binding Sites biology Chemistry Anti-Inflammatory Agents Non-Steroidal Organic Chemistry Amides In vitro Rats Enzyme inhibitor biology.protein Molecular Medicine Allosteric Site Protein Binding
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 20:4819-4824
ISSN:	0960-894X
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::646db32d2692e24d80d296daacfeccd7 https://doi.org/10.1016/j.bmcl.2010.06.102 Zobrazit plný text záznamu Full Text from ScienceDirect