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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)

Gomaa, Mohamed Sayed, Bridgens, Caroline E., Veal, Gareth J., Redfern, Christoper P.F., Brancale, Andrea, Armstrong, Jane L. and Simons, Claire 2011. 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). Journal of Medicinal Chemistry 54 (19) , pp. 6803-6811. 10.1021/jm200695m

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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) (IC50 = 0.35 nM as compared with liarozole IC50 = 540 nM and R116010 IC50 = 10 nM) was evaluated for CYP selectivity and hepatic stability. Compounds with CYP26 inhibitory IC50 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Publisher: American Chemical Society
ISSN: 0022-2623
Last Modified: 02 Jun 2019 22:51
URI: http://orca-mwe.cf.ac.uk/id/eprint/7448

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