title: 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 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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Que., Canada. bernard_cote@merck.com
authors.forename: Bernard
authors.initials: B
authors.lastname: Côté
authors.forename: Louise
authors.initials: L
authors.lastname: Boulet
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: David
authors.initials: D
authors.lastname: Claveau
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: André
authors.initials: A
authors.lastname: Giroux
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: D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced; D007093:Imidazoles / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010616:Phenanthrenes / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D018712:Analgesics, Non-Narcotic; D007093:Imidazoles; C526699:MF63 compound; D010616:Phenanthrenes; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases