5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38α MAP kinase

…, ST Wrobleski, J Lin, G Ahmed, A Metzger…

Index: Liu, Chunjian; Wrobleski, Stephen T.; Lin, James; Ahmed, Gulzar; Metzger, Axel; Wityak, John; Gillooly, Kathleen M.; Shuster, David J.; McIntyre, Kim W.; Pitt, Sidney; Shen, Ding Ren; Zhang, Rosemary F.; Zhang, Hongjian; Doweyko, Arthur M.; Diller, David; Henderson, Ian; Barrish, Joel C.; Dodd, John H.; Schieven, Gary L.; Leftheris, Katerina Journal of Medicinal Chemistry, 2005 , vol. 48, # 20 p. 6261 - 6270

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Citation Number: 41

Abstract

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 ...