Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors.
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.
Côté
Bernard
B
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Que., Canada. bernard_cote@merck.com
Boulet
Louise
L
Brideau
Christine
C
Claveau
David
D
Ethier
Diane
D
Frenette
Richard
R
Gagnon
Marc
M
Giroux
André
A
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
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
D018712:Analgesics, Non-Narcotic; D007093:Imidazoles; C526699:MF63 compound; D010616:Phenanthrenes; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases