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

  • Bioorg Med Chem Lett. 2007 Dec 15;17(24):6816-20. doi: 10.1016/j.bmcl.2007.10.033.
Bernard Côté  1 ,  Louise Boulet ,  Christine Brideau ,  David Claveau ,  Diane Ethier ,  Richard Frenette ,  Marc Gagnon ,  André Giroux ,  Jocelyne Guay ,  Sébastien Guiral ,  Joseph Mancini ,  Evelyn Martins ,  Frédéric Massé ,  Nathalie Méthot ,  Denis Riendeau ,  Joel Rubin ,  Daigen Xu ,  Hongping Yu ,  Yves Ducharme ,  Richard W Friesen
Affiliations
  • 1. Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Que., Canada. [email protected]
PMID: 18029174 DOI: 10.1016/j.bmcl.2007.10.033
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.