2. Academic Validation
  3. 5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase

5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase

  • J Med Chem. 2005 Oct 6;48(20):6261-70. doi: 10.1021/jm0503594.
Chunjian Liu 1,  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
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543-4000, USA.
PMID: 16190753 DOI: 10.1021/jm0503594
Abstract

A novel class of 5-cyanopyrimidine-based inhibitors of p38alpha 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 p38alpha.

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