title: Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886.
abstract: 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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Que., Canada H9H 3L1. denis_riendeau@merck.com
authors.forename: Denis
authors.initials: D
authors.lastname: Riendeau
authors.forename: Renee
authors.initials: R
authors.lastname: Aspiotis
authors.forename: Diane
authors.initials: D
authors.lastname: Ethier
authors.forename: Yves
authors.initials: Y
authors.lastname: Gareau
authors.forename: Erich L
authors.initials: EL
authors.lastname: Grimm
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Guay
authors.forename: Sébastien
authors.initials: S
authors.lastname: Guiral
authors.forename: Hélène
authors.initials: H
authors.lastname: Juteau
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Mancini
authors.forename: Nathalie
authors.initials: N
authors.lastname: Méthot
authors.forename: Joel
authors.initials: J
authors.lastname: Rubin
authors.forename: Richard W
authors.initials: RW
authors.lastname: Friesen
mesh_terms: 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
chemical_list: 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