Abstract
Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 microM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development.
MeSH terms
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Administration, Oral
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Animals
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacokinetics
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Disease Models, Animal
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Guinea Pigs
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Humans
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Hyperalgesia / drug therapy
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Intramolecular Oxidoreductases / antagonists & inhibitors*
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Intramolecular Oxidoreductases / metabolism
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Nitriles / chemical synthesis
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Nitriles / chemistry*
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Nitriles / pharmacokinetics
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Phenanthrenes / chemical synthesis
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Phenanthrenes / chemistry*
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Phenanthrenes / pharmacokinetics
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Prostaglandin-E Synthases
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
Substances
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Benzimidazoles
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Enzyme Inhibitors
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Nitriles
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Phenanthrenes
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Recombinant Proteins
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Intramolecular Oxidoreductases
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PTGES protein, human
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Prostaglandin-E Synthases