Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors

  • Bioorg Med Chem Lett. 2009 Oct 15;19(20):5837-41. doi: 10.1016/j.bmcl.2009.08.085.
André Giroux  1 ,  Louise Boulet ,  Christine Brideau ,  Anh Chau ,  David Claveau ,  Bernard Côté ,  Diane Ethier ,  Richard Frenette ,  Marc Gagnon ,  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 H9H 3L1. [email protected]
PMID: 19748780 DOI: 10.1016/j.bmcl.2009.08.085
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.