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

Jonathan L. Vennerstrom, Thomas J. Holmes

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Recent reports of serious concern regarding the safe 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 none of the reported nonbutylated malonamides was as 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.

Original languageEnglish (US)
Pages (from-to)434-437
Number of pages4
JournalJournal of Medicinal Chemistry
Volume30
Issue number2
DOIs
StatePublished - Feb 1 1987

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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