Anderson David R, Meyers Marvin J, Vernier William F, Mahoney Matthew W, Kurumbail Ravi G, Caspers Nicole, Poda Gennadiy I, Schindler John F, Reitz David B, Mourey Robert J
Pfizer Global Research and Development, St. Louis Laboratories, 700 Chesterfield Parkway W, Chesterfield, Missouri 63017, USA.
J Med Chem. 2007 May 31;50(11):2647-54. doi: 10.1021/jm0611004. Epub 2007 May 5.
A new class of potent kinase inhibitors selective for mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK-2) for the treatment of rheumatoid arthritis has been prepared and evaluated. These inhibitors have IC50 values as low as 10 nM against the target and have good selectivity profiles against a number of kinases including CDK2, ERK, JNK, and p38. These MK-2 inhibitors have been shown to suppress TNFalpha production in U397 cells and to be efficacious in an acute inflammation model. The structure-activity relationships of this series, the selectivity for MK-2 and their activity in both in vitro and in vivo models are discussed. The observed selectivity is discussed with the aid of an MK-2/inhibitor crystal structure.
已制备并评估了一类新型的、对丝裂原活化蛋白激酶激活的蛋白激酶2（MAPKAP-K2或MK-2）具有选择性的强效激酶抑制剂，用于治疗类风湿性关节炎。这些抑制剂对该靶点的IC50值低至10 nM，并且对包括CDK2、ERK、JNK和p38在内的多种激酶具有良好的选择性。这些MK-2抑制剂已被证明可抑制U397细胞中TNFα的产生，并在急性炎症模型中有效。讨论了该系列的构效关系、对MK-2的选择性及其在体外和体内模型中的活性。借助MK-2/抑制剂晶体结构对观察到的选择性进行了讨论。
