Synthesis of Sulfaphenazole Derivatives and Their Use as Inhibitors and Tools for Comparing the Active Sites of Human Liver Cytochromes P450 of the 2C Subfamily

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Abstract
Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes. These compounds are derived from SPA by replacement of the NH2 and H (of the SO2NH function) substituents of SPA with various R1 and R2 groups, respectively. Their inhibitory effects were studied on recombinant CYP 2C8, 2C9, 2C18, and 2C19 expressed in yeast. High affinities for CYP 2C9 (IC50 < 1 μM) were only observed for SPA derivatives having the SO2NH function and a relatively small R1 substituent (R1 = NH2, CH3). Any increase in the size of R1 led to a moderate decrease of the affinity, and the N-alkylation of the SO2NH function of SPA to a greater decrease of this affinity. The same structural changes led to opposite effects on molecular recognition by CYP 2C8 and 2C18, which generally exhibited similar behaviors. Thus, contrary to CYP 2C9, CYP 2C8 and 2C18 generally prefer neutral compounds with relatively large R1 and R2 substituents. CYP 2C19 showed an even lower affinity for anionic compounds than CYP 2C8 and 2C18. However, as CYP 2C8 and 2C18, CYP 2C19 showed a much better affinity for neutral compounds derived from N-alkylation of SPA and for anionic compounds bearing a larger R1 substituent. One of the new compounds (R1 = methyl, R2 = propyl) inhibited all human CYP 2Cs with IC50 values between 10 and 20 μM, while another one (R1 = allyl, R2 = methyl) inhibited all CYP 2Cs except CYP 2C9, and a third one (R1 = R2 = methyl) inhibited all CYP 2Cs except CYP 2C8. Only 2 compounds of the 25 tested derivatives were highly selective toward one human CYP 2C; these are SPA and compound 1 (R1 = CH3, R2 = H), which acted as selective CYP 2C9 inhibitors. However, some SPA derivatives selectively inhibited CYP 2C8 and 2C18. Since CYP 2C18 is hardly detectable in human liver, these derivatives could be interesting molecules to selectively inhibit CYP 2C8 in human liver microsomes. Thus, compound 11 (R1 = NH2, R2 = (CH2)2CH(CH3)2) appears to be particularly interesting for that purpose as its IC50 value for CYP 2C8 is low (3 μM) and 20-fold smaller than those found for CYP 2C9 and 2C19.

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