Prostaglandin-H Synthase Inhibition by Malonamides. Ring-Opened Analogues of Phenylbutazone

Article abstract of DOI:10.1021/jm00385a031

Recent reports of serious concern regarding the sfe clinical use of phenylbutazone and its hydroxylated metabolite (oxyphenbutazone) as antiinflammatory agents have prompted the further investigation of ring-opened (malonamide) derivatives as potentially preferable therapeutic derivatives.Earlier reports have claimed reduced toxicity among similar derivatives.These studies reveal the relative degree of prostaglandin-H (PGH) synthase inhibitory activity among a series of malonamide derivatives.Contrary to observations in the pyrazolidinedione series, incorporation of a nonpolar butyl side chain in these malonamides was not beneficial but, rather, detrimental to enzyme-inhibitory activity.Although nine of the reported nonbutylated malonamides was a potent an inhibitor of this enzyme as phenylbutazone, they all showed some inhibitory activity.PGH synthase inhibitory activity was especially pronounced in the bis(p-hydroxy anilide) derivatives, even extending to succinamide and adipamide derivatives.Of some interest is the observation that all of these p-hydroxy anilide derivatives were more potent inhibitors of this enzyme than acetaminophen.