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OtherAccelerated Communication

A NEW CLASS OF CYP2C9 INHIBITORS: PROBING 2C9 SPECIFICITY WITH HIGH-AFFINITY BENZBROMARONE DERIVATIVES

Charles W. Locuson II, Jan L. Wahlstrom, Denise A. Rock, Dan A. Rock and Jeffrey P. Jones
Drug Metabolism and Disposition July 2003, 31 (7) 967-971; DOI: https://doi.org/10.1124/dmd.31.7.967
Charles W. Locuson II
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Jan L. Wahlstrom
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Denise A. Rock
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Dan A. Rock
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Abstract

Noncovalent forces, other than hydrophobic interactions, are important determinants of substrate bias exhibited by some cytochromes P450. The CYP2C9 pharmacophore is proposed to include either an anionic group or hydrogen bond donor in addition to its hydrophobic groups. By constructing analogs of benzbromarone, evidence supporting the existence of a 2C9 anion-binding site was revealed. A nonsubstituted phenol analog was determined to have a pKa of 8.4 and a Ki of 414 nM whereas those with dihalogenated benzoyl phenols had pKa values between 4.2 to 5.2 and Ki values as low as 1 nM. The nonhalogenated, nonionizable analog is the poorest binder at 796 nM. The Ki range covers around three orders of magnitude with even the weakest binder being a more potent inhibitor than 2C9 substrate phenytoin. Thus, benzbromarone derivatives represent a class of molecules with the potential to reveal more structural details of the 2C9 active site.

Footnotes

  • ↵1 Abbreviations used are: P450, cytochrome P450; Bzbr, benzbromarone; cytb5, cytochrome b5.

  • Supported by National Institutes of Health Grants GM032165 and ES009122

    • Received February 24, 2003.
    • Accepted March 19, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (7)
Drug Metabolism and Disposition
Vol. 31, Issue 7
1 Jul 2003
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A NEW CLASS OF CYP2C9 INHIBITORS: PROBING 2C9 SPECIFICITY WITH HIGH-AFFINITY BENZBROMARONE DERIVATIVES

Charles W. Locuson, Jan L. Wahlstrom, Denise A. Rock, Dan A. Rock and Jeffrey P. Jones
Drug Metabolism and Disposition July 1, 2003, 31 (7) 967-971; DOI: https://doi.org/10.1124/dmd.31.7.967

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OtherAccelerated Communication

A NEW CLASS OF CYP2C9 INHIBITORS: PROBING 2C9 SPECIFICITY WITH HIGH-AFFINITY BENZBROMARONE DERIVATIVES

Charles W. Locuson, Jan L. Wahlstrom, Denise A. Rock, Dan A. Rock and Jeffrey P. Jones
Drug Metabolism and Disposition July 1, 2003, 31 (7) 967-971; DOI: https://doi.org/10.1124/dmd.31.7.967
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