Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors.
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.
Giroux
André
A
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Que., Canada H9H 3L1. andre_giroux@merck.com
Boulet
Louise
L
Brideau
Christine
C
Chau
Anh
A
Claveau
David
D
Côté
Bernard
B
Ethier
Diane
D
Frenette
Richard
R
Gagnon
Marc
M
Guay
Jocelyne
J
Guiral
Sébastien
S
Mancini
Joseph
J
Martins
Evelyn
E
Massé
Frédéric
F
Méthot
Nathalie
N
Riendeau
Denis
D
Rubin
Joel
J
Xu
Daigen
D
Yu
Hongping
H
Ducharme
Yves
Y
Friesen
Richard W
RW
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
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D009570:Nitriles; D010616:Phenanthrenes; D011994:Recombinant Proteins; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases