A new class of CYP2C9 inhibitors: probing 2C9 specificity with high-affinity benzbromarone derivatives.

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Locuson CW 2nd, Wahlstrom JL, Rock DA, Rock DA, Jones JP

A new class of CYP2C9 inhibitors: probing 2C9 specificity with high-affinity benzbromarone derivatives.

Drug Metab Dispos. 2003 Jul;31(7):967-71.

PubMed ID

12814975 [ View in PubMed

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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.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Benzbromarone	Cytochrome P450 2C9	Protein	Humans	Unknown	Inhibitor	Details