Preparation and Evaluation of Electrophilic Derivatives of Phenylbutazone as Inhibitors of Prostaglandin-H Synthase

Jonathan L. Vennerstrom, Thomas J. Holmes

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The chemical syntheses and biological evaluation of several potential irreversible inhibitors for prostaglandin (PGH) synthase are described. These inhibitors were modeled after the nonsteroidal antiinflammatory (NSAI) drug phenylbutazone (4-n-butyl-l,2-diphenyl-3,5-pyrazolidinedione). Electrophilic functionalities such as an a-bromo-acetamide, an a-chloroacetamide, a phenylurethane, a propargyl chloride, and several a,j3-unsaturated Michael acceptors were incorporated at the 4-position of the pyrazolidinedione ring structure. None of the derivatives showed evidence of irreversible inhibition of PGH synthase, although several were nearly as potent inhibitors of this enzyme as phenylbutazone. The nitrile obtained from 1,4-conjugate addition of cyanide to one of the unsaturated derivatives was considerably more potent as an inhibitor of PGH synthase than was phenylbutazone.

Original languageEnglish (US)
Pages (from-to)563-567
Number of pages5
JournalJournal of Medicinal Chemistry
Issue number3
StatePublished - Mar 1 1987


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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