Abstract information for the 2013 ICCP450 Meeting

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HYDANTOIN AND BARBITURATE INHIBITORS OF CYP2C19 AND CYP2C9
Hisashi Suzuki1, Byron Kneller1, Sreedhara Rao2, Jeffrey P. Jones2, and Allan E. Rettie*1
1Dept. of Medicinal Chemistry, University of Washington, Seattle, WA 98195 USA, 2Dept. of Chemistry, Washington State University, Pullman, WA 99164 USA. (rettie@uw.edu).

 

Consideration of the relative affinities of CYP2C9 and CYP2C19 for phenytoin and mephenytoin suggests that alkylation at the N-3 position on the hydantoin ring is an important determinant of isoform selectivity. Therefore, in order to refine our existing CoMFA model for CYP2C9 (Jones et al., DMD 24:1, 1996) and permit construction of a new model for CYP2C19, we synthesised three series of N-3 substituted phenytoin, nirvanol and phenobarbital derivatives and determined their Ki values against recombinant CYP2C9 and CYP2C19. Enantiomers in the phenobarbital and nirvanol series were resolved such that the inhibitory potencies of a total of 24 compounds were evaluated with each isoform. (S)-Flurbiprofen 4'-hydroxylation and 3-O-methylfluorescein O-demethylation served as highly sensitive fluorescent reporter HPLC assays for reconstituted CYP2C9 and CYP2C19, respectively. Almost all the N-3 alkyl substituted compounds were found to be competitive inhibitors of both isoforms, although the degree of inhibition was always much greater for CYP2C19. Inhibition was also pronouncedly stereoselective for CYP2C19, but not CYP2C9. (R)-3-Benzyl-phenobarbital emerged as the most potent inhibitor in the series with a Ki towards CYP2C19 of 80 nM. The construction of new CoMFA models for CYP2C9 and CYP2C19 based on these data is now in progress.

 

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