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

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 19 nM and moderate selectivity against a kinase panel. Com...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010, Vol.20 (1), p.334-337
Hauptverfasser:	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.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacokinetics Binding Sites Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Computer Simulation Crystallography, X-Ray Diaminopyrimidine Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - metabolism MAPKAP-K2 Medical sciences MK2 Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacokinetics Rats Rats, Sprague-Dawley Structure-Activity Relationship TNFα Tumor Necrosis Factor-alpha - metabolism
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Zusammenfassung:	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 19 nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFα production in peripheral human monocytes.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.10.103