Optimization of alpha-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site.
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.
Montalban
Antonio Garrido
AG
Drug Discovery, Kémia, Inc., 5871 Oberlin Drive, Suite 100, San Diego, CA 92121, USA. catalaba@hotmail.com
Boman
Erik
E
Chang
Chau-Dung
CD
Ceide
Susana Conde
SC
Dahl
Russell
R
Dalesandro
David
D
Delaet
Nancy G J
NG
Erb
Eric
E
Ernst
Justin T
JT
Gibbs
Andrew
A
Kahl
Jeffrey
J
Kessler
Linda
L
Kucharski
Jeff
J
Lum
Christopher
C
Lundström
Jan
J
Miller
Stephen
S
Nakanishi
Hiroshi
H
Roberts
Edward
E
Saiah
Eddine
E
Sullivan
Robert
R
Urban
Jan
J
Wang
Zhijun
Z
Larson
Christopher J
CJ
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
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases