title: Trisubstituted ureas as potent and selective mPGES-1 inhibitors.
abstract: A novel series of trisubstituted ureas has been identified as potent and selective mPGES-1 inhibitors. These compounds are selective over other prostanoid enzymes such as PGF synthase and TX synthase. This series of inhibitors was developed by lead optimization of a hit from an internal HTS campaign. Lead compound 42 is potent in A549 cell assay (IC(50) of 0.34 μM) and in human whole blood assay (IC(50) of 2.1 μM). An efficient and versatile one-pot strategy for the formation of ureas, involving a reductive amination, was developed to generate these inhibitors.
authors.affiliation: Merck Frosst Center for Therapeutic Research, Kirkland, Quebec, Canada. jfchiasson@gmail.com
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Chiasson
authors.forename: Louise
authors.initials: L
authors.lastname: Boulet
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: Anh
authors.initials: A
authors.lastname: Chau
authors.forename: David
authors.initials: D
authors.lastname: Claveau
authors.forename: Bernard
authors.initials: B
authors.lastname: Côté
authors.forename: Diane
authors.initials: D
authors.lastname: Ethier
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: 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: Patrick
authors.initials: P
authors.lastname: Roy
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: D045744:Cell Line, Tumor; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008861:Microsomes / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship; D014508:Urea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D014508:Urea; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases