Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors

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 μM (50% FBS) and a human whole blood IC 50 of 1.3 μM. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model when orally dosed at 30 and 100 mg/kg.