Etodolac, a novel antiinflammatory agent. The syntheses and biological evaluation of its metabolites.
The syntheses of five metabolites of the antiinflammatory drug etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid) are described, viz. 6-hydroxyetodolac, N-methyletodolac, 4-ureidoetodolac, 8-(1'-hydroxy)etodolac, and 4-oxoetodolac. These syntheses were used to confirm the identities of the metabolites. The metabolites themselves, as well as the previously reported metabolite 7-hydroxyetodolac, were tested in a rat adjuvant edema model and in vitro for their capacity to block prostaglandin production in chondrocyte cells. All either were inactive or possessed only marginal activity. The isolation of N-methyletodolac and 4-oxoetodolac from human and rat urine, respectively, is also described.
Humber
L G
LG
Ayerst Laboratories Research, Inc., Princeton, New Jersey 08543-8000.
Ferdinandi
E
E
Demerson
C A
CA
Ahmed
S
S
Shah
U
U
Mobilio
D
D
Sabatucci
J
J
De Lange
B
B
Labbadia
F
F
Hughes
P
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone; D004487:Edema / Q000188:drug therapy; D017308:Etodolac; D006801:Humans; D007210:Indoleacetic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000652:urine; D008297:Male; D008745:Methylation; D010084:Oxidation-Reduction; D011458:Prostaglandins E / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007210:Indoleacetic Acids; D011458:Prostaglandins E; D017308:Etodolac; D015232:Dinoprostone