title: Optimization of alpha-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site.
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.
authors.affiliation: Drug Discovery, Kémia, Inc., 5871 Oberlin Drive, Suite 100, San Diego, CA 92121, USA. catalaba@hotmail.com
authors.forename: Antonio Garrido
authors.initials: AG
authors.lastname: Montalban
authors.forename: Erik
authors.initials: E
authors.lastname: Boman
authors.forename: Chau-Dung
authors.initials: CD
authors.lastname: Chang
authors.forename: Susana Conde
authors.initials: SC
authors.lastname: Ceide
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: David
authors.initials: D
authors.lastname: Dalesandro
authors.forename: Nancy G J
authors.initials: NG
authors.lastname: Delaet
authors.forename: Eric
authors.initials: E
authors.lastname: Erb
authors.forename: Justin T
authors.initials: JT
authors.lastname: Ernst
authors.forename: Andrew
authors.initials: A
authors.lastname: Gibbs
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kahl
authors.forename: Linda
authors.initials: L
authors.lastname: Kessler
authors.forename: Jeff
authors.initials: J
authors.lastname: Kucharski
authors.forename: Christopher
authors.initials: C
authors.lastname: Lum
authors.forename: Jan
authors.initials: J
authors.lastname: Lundström
authors.forename: Stephen
authors.initials: S
authors.lastname: Miller
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
authors.forename: Robert
authors.initials: R
authors.lastname: Sullivan
authors.forename: Jan
authors.initials: J
authors.lastname: Urban
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Larson
mesh_terms: D000284:Administration, Oral; D000495:Allosteric Site; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases