Document Detail


The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase.
MedLine Citation:
PMID:  15566298     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38 alpha protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.
Authors:
Katerina Leftheris; Gulzar Ahmed; Ran Chan; Alaric J Dyckman; Zahid Hussain; Kan Ho; John Hynes; Jeffrey Letourneau; Wei Li; Shuqun Lin; Axel Metzger; Kevin J Moriarty; Chris Riviello; Yvonne Shimshock; James Wen; John Wityak; Stephen T Wrobleski; Hong Wu; Junjun Wu; Madhuri Desai; Kathleen M Gillooly; Tsung H Lin; Derek Loo; Kim W McIntyre; Sidney Pitt; Ding Ren Shen; David J Shuster; Rosemary Zhang; David Diller; Arthur Doweyko; John Sack; Jack Baldwin; Joel Barrish; John Dodd; Ian Henderson; Steve Kanner; Gary L Schieven; Maria Webb
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  47     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-29     Completed Date:  2005-01-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6283-91     Citation Subset:  IM    
Affiliation:
Departments of Discovery Chemistry, Bristol-Myers Squibb, PO Box 4000, Princeton, New Jersey 08543-4000, USA. katerina.leftheris@bms.com
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Amides / chemical synthesis*,  chemistry,  pharmacology
Aniline Compounds / chemical synthesis*,  chemistry,  pharmacology
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*,  chemistry,  pharmacology
Arthritis, Experimental / drug therapy,  pathology
Benzamides / chemical synthesis*,  chemistry,  pharmacology
Crystallography, X-Ray
Female
Humans
Mice
Mice, Inbred BALB C
Microsomes, Liver / drug effects,  metabolism
Models, Molecular
Molecular Structure
Monocytes / drug effects,  metabolism
Rats
Rats, Inbred Lew
Structure-Activity Relationship
Triazines / chemical synthesis*,  chemistry,  pharmacology
Tumor Necrosis Factor-alpha / biosynthesis
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*,  chemistry
Chemical
Reg. No./Substance:
0/Amides; 0/Aniline Compounds; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Benzamides; 0/N-methoxy-4-methyl-3-(4-(methyl(neopentyl)amino)-6-(4-methyl-1,4-diazepan-1-yl)-1,3,5-triazin-2-ylamino)benzamide; 0/Triazines; 0/Tumor Necrosis Factor-alpha; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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