5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38a MAP kinase

Chunjian Liu, Stephen T. Wrobleski, James Lin, Gulzar Ahmed, Axel Metzger, John Wityak, Kathleen M. Gillooly, David J. Shuster, Kim W. McIntyre, Sidney Pitt, Ding Ren Shen, Rosemary F. Zhang, Hongjian Zhang, Arthur M. Doweyko, David Diller, Ian Henderson, Joel C. Barrish, John H. Dodd, Gary L. Schieven, Katerina Leftheris

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62 Scopus citations


A novel class of 5-cyanopyrimidine-based inhibitors of p38a MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (>50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38α.

Original languageEnglish (US)
Pages (from-to)6261-6270
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number20
StatePublished - Oct 6 2005

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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