A new class of CYP2C9 inhibitors: probing 2C9 specificity with high-affinity benzbromarone derivatives.
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.
Locuson
Charles W
CW
Washington State University, School of molecular Biosciences, Pullman, WA 99164-4630, USA.
Wahlstrom
Jan L
JL
Rock
Denise A
DA
Rock
Dan A
DA
Jones
Jeffrey P
JP
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects*; D001553:Benzbromarone / Q000819:agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001665:Binding Sites; D065729:Cytochrome P-450 CYP2C9; D015335:Molecular Probes; D015394:Molecular Structure; D011487:Protein Conformation; D012680:Sensitivity and Specificity
D015335:Molecular Probes; D001553:Benzbromarone; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases