The synthesis of a series of 2-anilinophenylacetic acids, close analogues of diclofenac, is described. These compounds were tested in two models used for evaluating the activity of nonsteroidal antiinflammatory drugs (NSAID's), inhibition of cyclooxygenase enzyme activity in vitro, and adjuvant-induced arthritis (AdA) in rats. Statistically significant correlations were found between the inhibitory activities of the compounds in these two models, indicating that cyclooxygenase inhibition seems to be the underlying mechanism for the antiinflammatory activity of these compounds. Quantitative structure-activity relationship (QSAR) analysis revealed that the crucial parameters for activity in both models were the lipophilicity and the angle of twist between the two phenyl rings. Optimal activities were associated with halogen or alkyl substituents in both ortho positions of the anilino ring. Compounds with OH groups in addition to two ortho substituents or compounds with only one or no ortho substituents were less active.

Diclofenac sodium (Voltaren") is a non-steroid anti-inflammatory agent of a new chemical structure, which in animal experiments shows a high degree of antiinflammatory, analgesic, and antipyretic activity in various pharmacological models. It inhibits prostaglandin biosynthesis in vitro and in vivo, and this inhibitory effect at least partly explains the mechanism of action of the preparation. In animal experiments diclofenac sodium is characterised by a broad therapeutic range. Also, its gastrointestinal tolerability is better than that of other highly effective non-steroid anti-inhmmatory agents. Two of the metabolites produced during the biotransformation of diclofenac sodium in man are also biologically active. The activity of these two metabolites, however, is very much weaker than that of unchanged diclofenac sodium and is comparable to that of phenylbutazone. S a n d J Rheumutology, Suppl. 22 Scand J Rheumatol Downloaded from informahealthcare.com by University of Guelph on 10/19/12 For personal use only. Scand J Rheumatology. Suppl. 22 Scand J Rheumatol Downloaded from informahealthcare.com by University of Guelph on 10/19/12 For personal use only. Scand J Rheurnatology. Suppl. 22 Scand J Rheumatol Downloaded from informahealthcare.com by University of Guelph on 10/19/12 For personal use only. 'I Dose leading to a blood loss of IS0 wl/72 h. ' ' No effect observed at this dose level. ' Marginal. though statistically significant, increase over the control level observed at 300 mg/kg p.0. '' No mortality observed at this dose level. Metabolite I M > I 0 0 18 M 240 (203-287) 70 70 60 60 70 70 20 50Scand J Rheumatol Downloaded from informahealthcare.com by University of Guelph on 10/19/12For personal use only.

1. The anti-inflammatory agent diclofenac sodium (o-[(2,6-dichlorophenyl)amino]phenylacetic acid sodium salt) is extensively metabolized by rat, dog, baboon and man. The main metabolites were isolated from the urine of all species and from the bile of rat and dog and identified by spectroscopy. 2. Metabolism involves direct conjugation of the unchanged drug, or oxidation of the aromatic rings usually followed by conjugation. Sites of oxidation are either position 3' or 4' of the dichlorophenyl ring or, alternatively, position 5 of the phenyl ring attached to the acetic acid moiety. 3. In the urine of rat, baboon and man conjugates of the hydroxylated metabolites predominate, but the major metabolite in dog urine is the taurine conjugate of unchanged diclofenac. 4. In the bile of rat and dog, the main metabolite is the ester glucuroniade of unchanged diclofenac.

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Five metabolites of diclofenac sodium (Voltarol) have been identified in human plasma. All five metabolites were more than 50 times less potent than diclofenac in inhibiting PGE2 production in zymosan-stimulated mouse macrophages and LTC4 synthesis was not inhibited in these cells. Anti-inflammatory activity (adjuvant arthritis and carragheenan-induced paw oedema in rats) and analgesic activity (phenyl-p-benzoquinone writhing, mouse) of the metabolites were at least 10 times lower when compared to diclofenac. There was a good correlation between in vitro PGE2 inhibition and in vivo activities for diclofenac and its metabolites indicating that inhibition of prostaglandin synthesis is a major mechanism responsible for their pharmacological actions.

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