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5-Cyanopyrimidine Derivatives as a Novel Class of Potent, Selective, and Orally Active Inhibitors of p38α MAP Kinase

2005; American Chemical Society; Volume: 48; Issue: 20 Linguagem: Inglês

10.1021/jm0503594

1520-4804

Chunjian Liu, Stephen T. Wrobleski, James C. 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,

Quinazolinone synthesis and applications

A novel class of 5-cyanopyrimidine-based inhibitors of p38α 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.