title: Discovery of a potent and selective COX-2 inhibitor in the alkoxy lactone series with optimized metabolic profile.
abstract: The COX-2 inhibitor DFP [5,5-dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone] was found to have a long half-life in humans. Analogues have been characterized in order to optimize pharmacokinetics. This has lead to the discovery of 5(S)-(5-ethyl-5-methyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone analogue 11 a potent and selective COX-2 inhibitor which is metabolized to a greater extent than DFP upon incubation with rat and human hepatocytes, suggesting a shorter half-life in humans.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec, Canada. yves_leblanc@merck.com
authors.forename: Yves
authors.initials: Y
authors.lastname: Leblanc
authors.forename: Patrick
authors.initials: P
authors.lastname: Roy
authors.forename: Zhaoyin
authors.initials: Z
authors.lastname: Wang
authors.forename: Chun Sing
authors.initials: CS
authors.lastname: Li
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nicoll-Griffith
authors.forename: José M
authors.initials: JM
authors.lastname: Silva
authors.forename: Yves
authors.initials: Y
authors.lastname: Aubin
authors.forename: James A
authors.initials: JA
authors.lastname: Yergey
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Denis
authors.initials: D
authors.lastname: Riendeau
authors.forename: Christine
authors.initials: C
authors.lastname: Brideau
authors.forename: Robert
authors.initials: R
authors.lastname: Gordon
authors.forename: Lijing
authors.initials: L
authors.lastname: Xu
authors.forename: Janine
authors.initials: J
authors.lastname: Webb
authors.forename: Denise M
authors.initials: DM
authors.lastname: Visco
authors.forename: Petpiboon
authors.initials: P
authors.lastname: Prasit
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007783:Lactones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins; D010599:Pharmacokinetics; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin