RT Journal Article
SR Electronic
T1 A NEW CLASS OF CYP2C9 INHIBITORS: PROBING 2C9 SPECIFICITY WITH HIGH-AFFINITY BENZBROMARONE DERIVATIVES
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 967
OP 971
DO 10.1124/dmd.31.7.967
VO 31
IS 7
A1 Charles W. Locuson II
A1 Jan L. Wahlstrom
A1 Denise A. Rock
A1 Dan A. Rock
A1 Jeffrey P. Jones
YR 2003
UL http://dmd.aspetjournals.org/content/31/7/967.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics