title: Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors.
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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Que., Canada H9H 3L1. andre_giroux@merck.com
authors.forename: André
authors.initials: A
authors.lastname: Giroux
authors.forename: Louise
authors.initials: L
authors.lastname: Boulet
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: Anh
authors.initials: A
authors.lastname: Chau
authors.forename: David
authors.initials: D
authors.lastname: Claveau
authors.forename: Bernard
authors.initials: B
authors.lastname: Côté
authors.forename: Diane
authors.initials: D
authors.lastname: Ethier
authors.forename: Richard
authors.initials: R
authors.lastname: Frenette
authors.forename: Marc
authors.initials: M
authors.lastname: Gagnon
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Guay
authors.forename: Sébastien
authors.initials: S
authors.lastname: Guiral
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: Evelyn
authors.initials: E
authors.lastname: Martins
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massé
authors.forename: Nathalie
authors.initials: N
authors.lastname: Méthot
authors.forename: Denis
authors.initials: D
authors.lastname: Riendeau
authors.forename: Joel
authors.initials: J
authors.lastname: Rubin
authors.forename: Daigen
authors.initials: D
authors.lastname: Xu
authors.forename: Hongping
authors.initials: H
authors.lastname: Yu
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Richard W
authors.initials: RW
authors.lastname: Friesen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000071876:Prostaglandin-E Synthases; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D009570:Nitriles; D010616:Phenanthrenes; D011994:Recombinant Proteins; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases