Synthesis and biological evaluation of 2-phenylpyran-4-ones: a new class of orally active cyclooxygenase-2 inhibitors.
A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.
Caturla
Francisco
F
Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024 Barcelona, Spain.
Jiménez
Juan-Miguel
JM
Godessart
Núria
N
Amat
Mercè
M
Cárdenas
Alvaro
A
Soca
Lídia
L
Beleta
Jordi
J
Ryder
Hamish
H
Crespo
María I
MI
D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001798:Blood Proteins / Q000378:metabolism; D051546:Cyclooxygenase 2; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011485:Protein Binding; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D001798:Blood Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D011714:Pyrans; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases