The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase

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 DesaiKathleen 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

Research output: Contribution to journalArticle

52 Scopus citations

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 p38a 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.

Original languageEnglish (US)
Pages (from-to)6283-6291
Number of pages9
JournalJournal of Medicinal Chemistry
Volume47
Issue number25
DOIs
StatePublished - Dec 2 2004

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Leftheris, K., Ahmed, G., Chan, R., Dyckman, A. J., Hussain, Z., Ho, K., Hynes, J., Letourneau, J., Li, W., Lin, S., Metzger, A., Moriarty, K. J., Riviello, C., Shimshock, Y., Wen, J., Wityak, J., Wrobleski, S. T., Wu, H., Wu, J., ... Webb, M. (2004). The discovery of orally active triaminotriazine aniline amides as inhibitors of p38 MAP kinase. Journal of Medicinal Chemistry, 47(25), 6283-6291. https://doi.org/10.1021/jm049521d