Abstract
Here we describe the SAR of a series of potent and selective mPGES-1 inhibitors based on an oxicam template. Compound 13j demonstrated low nanomolar mPGES-1 inhibition in an enzyme assay. In addition, it displayed PGE(2) inhibition in a cell-based assay (0.42microM) and had over 238-fold selectivity for mPGES-1 over COX-2 and over 200-fold selectivity for mPGES-1 over 6-keto PGF(1alpha).
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / chemistry*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Cell Line
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Cyclic S-Oxides / chemical synthesis
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Cyclic S-Oxides / chemistry*
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Cyclic S-Oxides / pharmacology
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Humans
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Intramolecular Oxidoreductases / antagonists & inhibitors*
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Intramolecular Oxidoreductases / metabolism
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Prostaglandin-E Synthases
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Structure-Activity Relationship
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Thiazines / chemical synthesis
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Thiazines / chemistry*
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Thiazines / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclic S-Oxides
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Enzyme Inhibitors
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Thiazines
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Intramolecular Oxidoreductases
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PTGES protein, human
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Prostaglandin-E Synthases