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2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2010 Jan 01; Vol. 20 (1), pp. 334-7. Date of Electronic Publication: 2009 Oct 29. - Publication Year :
- 2010
-
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.<br /> (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Subjects :
- 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
Anti-Inflammatory Agents chemistry
Intracellular Signaling Peptides and Proteins antagonists & inhibitors
Protein Kinase Inhibitors chemistry
Protein Serine-Threonine Kinases antagonists & inhibitors
Pyrimidines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 20
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 19926477
- Full Text :
- https://doi.org/10.1016/j.bmcl.2009.10.103