2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors.
Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-difluorophenyl derivative 7 (L-776,967) and the 3-pyridyl derivative 13 (L-784,506) are particularly interesting as potential antiinflammatory agents with reduced side-effect profiles. Both exhibit good oral bioavailability and are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonsteroidal antiflammatory drugs.
Black
W C
WC
Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8, and Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
Brideau
C
C
Chan
C C
CC
Charleson
S
S
Chauret
N
N
Claveau
D
D
Ethier
D
D
Gordon
R
R
Greig
G
G
Guay
J
J
Hughes
G
G
Jolicoeur
P
P
Leblanc
Y
Y
Nicoll-Griffith
D
D
Ouimet
N
N
Riendeau
D
D
Visco
D
D
Wang
Z
Z
Xu
L
L
Prasit
P
P
D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001682:Biological Availability; D016466:CHO Cells; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D006224:Cricetinae; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004064:Digestive System / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D005334:Fever / Q000188:drug therapy; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008861:Microsomes / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014162:Transfection
D018712:Analgesics, Non-Narcotic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003517:Cyclopentanes; D007527:Isoenzymes; C118876:L 776967; C118877:L 784506; D008565:Membrane Proteins; D013450:Sulfones; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat