Discovery of a potent and selective COX-2 inhibitor in the alkoxy lactone series with optimized metabolic profile.
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.
Leblanc
Yves
Y
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec, Canada. yves_leblanc@merck.com
Roy
Patrick
P
Wang
Zhaoyin
Z
Li
Chun Sing
CS
Chauret
Nathalie
N
Nicoll-Griffith
Deborah A
DA
Silva
José M
JM
Aubin
Yves
Y
Yergey
James A
JA
Chan
Chi Chung
CC
Riendeau
Denis
D
Brideau
Christine
C
Gordon
Robert
R
Xu
Lijing
L
Webb
Janine
J
Visco
Denise M
DM
Prasit
Petpiboon
P
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
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