Thiopurine Methyltransferase: Structure-Activity Relationships for Benzoic Acid Inhibitors and Thiophenol Substrates

Matthew M. Ames, Cynthia Dias Selassie, Lee C. Woodson, Jon A. Van Loon, Corwin Hansch, Richard M. Weinshilboum

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Twenty-seven substituted benzoic acids have been studied as inhibitors of partially purified human renal thiopurine methyltransferase (TPMT). Quantitative structure-activity relationship (QSAR) analysis resulted in the following equation: pI50 = + + 2.92(±0.39). In this equation pI50 is the -log of the concentration of compound that inhibits the enzyme activity by 50% (IC50); is the relative hydrophobicity of the more hydrophobic of the two meta substituents; and MR3 4 is the molar refractivity of the more hydrophobic of the two meta substituents and of the para substituent on the phenyl ring. In addition, 14 substituted thiophenols were tested as substrates for the enzyme. All 14 thiophenols tested were excellent substrates with Kmconstants (0.8-7.8 μM) that were at least 2 orders of magnitude lower than those of any known thiopurine substrate for TPMT. However, there was no discernible relationship between the activities of thiophenol substrates and their physicochemical parameters. These results suggest that benzoic acid inhibitors of and thiophenol substrates for TPMT may interact with different sites on the enzyme.

Original languageEnglish (US)
Pages (from-to)354-358
Number of pages5
JournalJournal of Medicinal Chemistry
Volume29
Issue number3
DOIs
StatePublished - Jan 1 1986

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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