Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors
2007; Elsevier BV; Volume: 17; Issue: 24 Linguagem: Inglês
10.1016/j.bmcl.2007.10.033
ISSN1464-3405
AutoresBernard Côté, Louise Boulet, Christine Brideau, David Claveau, Diane Ethier, Richard Frenette, Marc Gagnon, André Giroux, Jocelyne Guay, Sébastien Guiral, Joseph A. Mancini, Evelyn Martins, Frédéric Massé, Nathalie Méthot, Denis Riendeau, Joel Rubin, Daigen Xu, Hongping Yu, Yves Ducharme, Richard W. Friesen,
Tópico(s)Enzyme function and inhibition
ResumoPhenanthrene 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 IC50 of 0.42 μM (50% FBS) and a human whole blood IC50 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.
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