Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series

Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.613-618
Hauptverfasser:	Oubrie, Arthur, Kaptein, Allard, de Zwart, Edwin, Hoogenboom, Niels, Goorden, Rianne, van de Kar, Bas, van Hoek, Maaike, de Kimpe, Vera, van der Heijden, Ruud, Borsboom, Judith, Kazemier, Bert, de Roos, Jeroen, Scheffers, Michiel, Lommerse, Jos, Schultz-Fademrecht, Carsten, Barf, Tjeerd
Format:	Artikel
Sprache:	eng
Schlagworte:	adenosine triphosphate Anti-TNFα Benzamides - pharmacology Biological and medical sciences Chemistry, Pharmaceutical - methods Computer Simulation Crystallography, X-Ray - methods Cytokines - metabolism Drug Design HSP27 HSP27 Heat-Shock Proteins - metabolism Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - pharmacology MAPKAPK2 Medical sciences MK2 Models, Chemical Pharmacology. Drug treatments Phosphorylation Piperidones - pharmacology Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - pharmacology Pyrroles - chemistry Rheumatoid arthritis tumor necrosis factor-alpha Tumor Necrosis Factor-alpha - metabolism X-ray diffraction
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Beschreibung
Zusammenfassung:	Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.10.071