2, 4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization

…, RW Dixon, KE Frank, EF Johnson, J Kamens…

Index: Harris, Christopher M.; Ericsson, Anna M.; Argiriadi, Maria A.; Barberis, Claude; Borhani, David W.; Burchat, Andrew; Calderwood, David J.; Cunha, George A.; Dixon, Richard W.; Frank, Kristine E.; Johnson, Eric F.; Kamens, Joanne; Kwak, Silvia; Li, Biqin; Mullen, Kelly D.; Perron, Denise C.; Wang, Lu; Wishart, Neil; Wu, Xiaoyun; Zhang, Xiaolei; Zmetra, Tami R.; Talanian, Robert V. Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 1 p. 334 - 337

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Citation Number: 19

Abstract

We describe structure-based optimization of a series of novel 2, 4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC50 values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFα production in peripheral human monocytes.