Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886.
A series of potent and selective inhibitors of the inducible microsomal PGE2 synthase (mPGES-1) has been developed based on the indole FLAP inhibitor MK-886. Compounds 23 and 30 inhibit mPGES-1 with potencies in the low nanomolar range and with selectivities of at least 100-fold compared to their inhibition of mPGES-2, thromboxane synthase and binding affinity to FLAP. They also block the production of PGE2 in cell based assays but with a decreased potency and more limited selectivity compared to the enzyme assays.
Riendeau
Denis
D
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Que., Canada H9H 3L1. denis_riendeau@merck.com
Aspiotis
Renee
R
Ethier
Diane
D
Gareau
Yves
Y
Grimm
Erich L
EL
Guay
Jocelyne
J
Guiral
Sébastien
S
Juteau
Hélène
H
Mancini
Joseph A
JA
Méthot
Nathalie
N
Rubin
Joel
J
Friesen
Richard W
RW
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008861:Microsomes / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship; D002722:Chlorobenzenes
D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C060893:MK-886; D002722:Chlorobenzenes; C000605862:PTGES protein, human; C000605863:PTGES2 protein, human