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Vol. 30, Issue 3, 235-239, March 2002
)-N-3-Benzyl-Phenobarbital: New Potent and Selective
in Vitro Inhibitors of CYP2C19
Department of Medicinal Chemistry, School of Pharmacy, University
of Washington, Seattle, Washington
Highly potent and selective CYP2C19 inhibitors are not currently
available. In the present study, N-3-benzyl derivatives
of nirvanol and phenobarbital were synthesized, their respective (+)-
and (
)-enantiomers resolved chromatographically, and inhibitor potencies determined for these compounds toward CYP2C19 and other human
liver cytochromes P450 (P450s).
()-N-3-Benzyl-phenobarbital and
(+)-N-3-benzyl-nirvanol were found to be highly potent,
competitive inhibitors of recombinant CYP2C19, exhibiting
Ki values of 79 and 250 nM, respectively,
whereas their antipodes were 20- to 60-fold less potent. In human liver
preparations, ()-N-3-benzyl-phenobarbital and
(+)-N-3-benzyl-nirvanol inhibited
(S)-mephenytoin 4'-hydroxylase activity, a marker for
native microsomal CYP2C19, with Ki values ranging from 71 to 94 nM and 210 to 280 nM, respectively. At single substrate concentrations of 0.3 µM
[()-N-3-benzyl-phenobarbital] and 1 µM
[(+)-N-3-benzyl-nirvanol] that were used to examine
inhibition of a panel of cDNA-expressed P450 isoforms, neither
CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, nor 3A4 activities were decreased by
greater than 16%. In contrast, CYP2C19 activity was inhibited ~80%
under these conditions. Therefore,
(+)-N-3-benzyl-nirvanol and
()-N-3-benzyl-phenobarbital represent new, highly
potent and selective inhibitors of CYP2C19 that are likely to prove
generally useful for screening purposes during early phases of drug
metabolism studies with new chemical entities.
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