Abstract
Phenanthrene imidazole 3 (MF63) has been identified as a novel potent, selective, and orally active mPGES-1 inhibitor. This new series was developed by lead optimization of a hit from an internal HTS campaign. Compound 3 is significantly more potent than the previously reported indole carboxylic acid 1 with an A549 whole cell IC(50) of 0.42 microM (50% FBS) and a human whole blood IC(50) of 1.3 microM. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model when orally dosed at 30 and 100mg/kg.
MeSH terms
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Analgesics, Non-Narcotic / blood
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Analgesics, Non-Narcotic / chemical synthesis*
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Analgesics, Non-Narcotic / chemistry
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Analgesics, Non-Narcotic / pharmacology
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Animals
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Disease Models, Animal
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Drug Design
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Guinea Pigs
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Humans
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Hyperalgesia / chemically induced
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Imidazoles / blood
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Inhibitory Concentration 50
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Intramolecular Oxidoreductases / antagonists & inhibitors*
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Molecular Structure
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Phenanthrenes / blood
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Phenanthrenes / chemical synthesis*
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Phenanthrenes / chemistry
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Phenanthrenes / pharmacology*
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Prostaglandin-E Synthases
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Rats
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Structure-Activity Relationship
Substances
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Analgesics, Non-Narcotic
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Imidazoles
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MF63 compound
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Phenanthrenes
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Intramolecular Oxidoreductases
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PTGES protein, human
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Prostaglandin-E Synthases