| Literature DB >> 15566298 |
Katerina Leftheris1, 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.
Abstract
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.Entities:
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Year: 2004 PMID： 15566298 DOI： 10.1021/jm049521d
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446