5,6,7,8-四氢吡啶并[4,3-d]嘧啶类化合物作为新型强效和高选择性 CaMKII 抑制剂。
5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidines as novel class of potent and highly selective CaMKII inhibitors.
机构信息
Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.
出版信息
Bioorg Med Chem Lett. 2010 Nov 15;20(22):6696-8. doi: 10.1016/j.bmcl.2010.09.005. Epub 2010 Sep 9.
A novel series of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines containing substituted phenyl sulfonamide are synthesized and evaluated for their inhibitory activity against CaMKII. Substituents on the phenyl group had significant impact on CaMKII inhibition, in particular, the inhibitory activity of 8p was 25-fold higher than that of KN-93, a known CaMKII inhibitor. Michaelis-Menten analysis of a representative compound suggested that the synthesized pyrimidines are calmodulin non-competitive inhibitors. Finally, 8p exhibited more than 100-fold higher selectivity for CaMKII over five types of off-target kinases.
合成了一系列新型的含取代苯基磺酰胺的 5,6,7,8-四氢吡啶并[4,3-d]嘧啶，并评估了它们对 CaMKII 的抑制活性。苯环上的取代基对 CaMKII 抑制有显著影响，特别是 8p 的抑制活性比已知的 CaMKII 抑制剂 KN-93 高 25 倍。代表性化合物的米氏分析表明，合成的嘧啶类化合物是钙调蛋白非竞争性抑制剂。最后，8p 对 CaMKII 的选择性比五种脱靶激酶高 100 多倍。
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