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

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.

Bioorg Med Chem Lett ; 20(1): 334-7, 2010 Jan 01.

Article in English | MEDLINE | ID: mdl-19926477

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 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.

Subject(s)

Anti-Inflammatory Agents/chemistry , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Administration, Oral , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Binding Sites , Computer Simulation , Crystallography, X-Ray , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism

ABSTRACT

Subject(s)

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