Synthesis and Biological Evaluation of 3-(1H-Imidazol- and Triazol-1-yl)-2,2-dimethyl-3-[4-(naphthalen-2-ylamino)phenyl]propyl Derivatives as Small Molecule Inhibitors of Retinoic Acid 4-Hydroxylase (CYP26)

Abstract

The synthesis and potent inhibitory activity of novel 3-(1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-(4-(naphthalen-2-ylamino)phenyl)propyl derivatives vs a MCF-7 CYP26A1 microsomal assay is described. This study focused on the effect of modifying the heme binding azole group and the flexible C3 chain on inhibitory activity and selectivity. The most promising inhibitor 2,2-dimethyl-3-[4-(naphthalen-2-ylamino)-phenyl]-3-[1,2,4]triazol-1-yl-propionic acid methyl ester (17) (IC(50) = 0.35 nM as compared with liarozole IC(50) = 540 nM and R116010 IC(50) = 10 nM) was evaluated for CYP selectivity and hepatic stability. Compounds with CYP26 inhibitory IC(50) values ≤50 nM enhanced the biological activity of exogenous ATRA, as evidenced by a 3.7-5.8-fold increase in CYP26A1 mRNA in SH-SY5Y neuroblastoma cells as compared with ATRA alone. All compounds demonstrated an activity comparable with or better than R116010, and the induction correlated well with CYP26 inhibition data. These studies highlight the promising activity profile of this novel CYP26 inhibitor and suggest it as an appropriate candidate for future development.

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

“…These minor changes did not significantly affect CYP26A1 inhibitory potency (Table 3) [27]. Because of the extensive number of studies done on liarozole, the efficacy of R116010 is often compared to that of liarozole in in vitro studies [27, 142, 167, 168]. R116010 was approximately 100-fold more potent than liarozole in inhibiting cell growth in human T47D breast cancer cells pretreated with ATRA (Table 4).…”

“…R116010 inhibited ATRA metabolism with an IC 50 value of 8.4 nM in comparison to the IC 50 of 1.4 μM for liarozole (Table 3) [142]. Co-incubation of R116010 (1 μM) with ATRA (0.1 μM) has also been shown to enhance the potency of ATRA in MCF-7 cells, as evidenced by a 4.7-fold greater induction of CYP26A1 mRNA expression in the presence of R116010 than with RA alone [167, 168]. In T47D microsomes with induced CYP26A1 expression, R116010 had an IC 50 of 4 nM against ATRA metabolism (Table 3), whereas it showed little inhibition of CYP2C11, CYP2A1, CYP3A or CYP2B1/2 catalyzed reactions in rat liver microsomes or CYP19 in human placental microsomes [142].…”

“…They have also used homology models of CYP26A1, built using the homologous RA metabolizing P450s, CYP2C8, CYP2C9, and CYP3A4 [158], with molecular docking to improve the understanding of CYP26A1 active site features [116, 167, 168, 171]. Interestingly, only the homology model built using CYP3A4 as a template could accommodate talarozole binding to the active site [158].…”

“…To further improve these imidazole containing inhibitors, further modifications were made using compound 8 as a lead compound by varying the composition of the linker between the naphthyl and benzyl groups, and by substituting the phenyl ring with a flexible C3 chain such as propionic acid methyl ester (the imidazole analogue of compound 9) [167, 168]. While altering the composition of the linker group decreased the binding affinity to CYP26A1 (IC 50 >1 μM), replacing the naphthyl with a phenyl generally preserved the nanomolar binding affinity of the inhibitors [167, 168].…”

“…While altering the composition of the linker group decreased the binding affinity to CYP26A1 (IC 50 >1 μM), replacing the naphthyl with a phenyl generally preserved the nanomolar binding affinity of the inhibitors [167, 168]. Replacement of the benzyl moiety with a propanoate led to about 10-fold increased potency towards CYP26A1 (Table 3).…”