Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors
Section snippets
Materials
(S)-Flurbiprofen, 4′-hydroxyflurbiprofen, and 2-fluoro-4-biphenylacetic acid were gifts from Dr. T.S. Tracy (West Virginia University, Morgantown, WV). Mephobarbital, 3-O-methylfluorescein, fluorescein, and 2,7-dichlorofluorescein were purchased from Sigma–Aldrich Chemical (St. Louis, MO). Nirvanol, mephenytoin, and (S)-nirvanol were prepared as reported previously [21]. TLC plates, POLYGRAM SIL G/UV254, were Macherey-Nagel from Alltech Associates (Deerfield, IL). All other chemicals and
Experimental approach
These studies were initiated in an effort to design new high-affinity inhibitors of CYP2C19 with which to begin constructing computational models for this enzyme. We chose to focus on hydantoin and barbiturate structures as templates because (S)-mephenytoin and mephobarbital are well-recognized selective substrates for CYP2C19 [32], and it had been reported that N-3 methylation of phenytoin enhanced affinity for CYP2C19 at the expense of CYP2C9 [33]. In each series, the readily available parent
Acknowledgements
This work was supported by NIH Grant GM32165 (W.F.T., J.P.J., and A.E.R.). The authors acknowledge the excellent technical assistance of Ms. Alison Bickerstaff.
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