Abstract
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC(50)<3 nM and inhibit the release of TNFalpha (IC(50)<0.3 microM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC(50)=0.05-0.23 microM), less potent in cells (IC(50)<1.1 microM), but show good oral absorption. Compound 13E (100mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Azetidinecarboxylic Acid / chemical synthesis
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Azetidinecarboxylic Acid / chemistry*
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Azetidinecarboxylic Acid / pharmacology
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Azetidines / chemistry
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Binding Sites
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Cell Line
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Crystallography, X-Ray
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Cyclopropanes / chemistry
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Cyclopropanes / pharmacology
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HSP27 Heat-Shock Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Spiro Compounds / chemistry
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Azetidines
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Cyclopropanes
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HSP27 Heat-Shock Proteins
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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Spiro Compounds
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Tumor Necrosis Factor-alpha
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azetidine
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Azetidinecarboxylic Acid
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cyclopropane
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases