Chemical and biological investigation of N-hydroxy-valdecoxib: An active metabolite of valdecoxib.
The inhibition of cyclooxygenase enzymes plays an important role in the treatment of inflammatory diseases. N-Hydroxy-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide (3)-a primary metabolite of the highly selective COX-2 inhibitor valdecoxib-was synthesized and stabilized as its monohydrate (3a.H(2)O). The anti-inflammatory properties of 3a.H(2)O were investigated in carrageenan-induced edema and in acute and chronic pain models. Based on our biological investigation, we conclude that N-hydroxy-valdecoxib 3a is an active metabolite of valdecoxib.
Erdélyi
Péter
P
Medicinal Chemistry Research Laboratory No. IV., Gedeon Richter Plc., PO Box 27, H-1475 Budapest 10, Hungary. p.erdelyi@richter.hu
Fodor
Tamás
T
Varga
Agnes Kis
AK
Czugler
Mátyás
M
Gere
Anikó
A
Fischer
János
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002351:Carrageenan; D002417:Cattle; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000379:methods; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000187:drug effects; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D000096926:Benzenesulfonamides
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D011994:Recombinant Proteins; D013449:Sulfonamides; C530909:N-hydroxy-valdecoxib; C406224:valdecoxib; D000096926:Benzenesulfonamides