Abstract
A series of potent and selective inhibitors of the inducible microsomal PGE2 synthase (mPGES-1) has been developed based on the indole FLAP inhibitor MK-886. Compounds 23 and 30 inhibit mPGES-1 with potencies in the low nanomolar range and with selectivities of at least 100-fold compared to their inhibition of mPGES-2, thromboxane synthase and binding affinity to FLAP. They also block the production of PGE2 in cell based assays but with a decreased potency and more limited selectivity compared to the enzyme assays.
MeSH terms
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclooxygenase Inhibitors / chemical synthesis*
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology*
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology*
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Intramolecular Oxidoreductases / antagonists & inhibitors*
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Microsomes / enzymology
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Prostaglandin-E Synthases
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Structure-Activity Relationship
Substances
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Cyclooxygenase Inhibitors
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Indoles
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MK-886
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Intramolecular Oxidoreductases
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PTGES protein, human
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PTGES2 protein, human
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Prostaglandin-E Synthases