- 2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.
2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.
Bioorganic & medicinal chemistry letters (2009-11-21)
Christopher M Harris, Anna M Ericsson, Maria A Argiriadi, Claude Barberis, David W Borhani, Andrew Burchat, David J Calderwood, George A Cunha, Richard W Dixon, Kristine E Frank, Eric F Johnson, Joanne Kamens, Silvia Kwak, Biqin Li, Kelly D Mullen, Denise C Perron, Lu Wang, Neil Wishart, Xiaoyun Wu, Xiaolei Zhang, Tami R Zmetra, Robert V Talanian
PMID19926477
摘要
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 IC(50) values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFalpha production in peripheral human monocytes.
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