Potent CYP19 (Aromatase) 1-[(Benzofuran-2-yl)(phenylmethyl)pyridine, -imidazole, and -triazole Inhibitors:  Synthesis and Biological Evaluation

Saberi, M. R., Vinh, T. K., Yee, S. W., Griffiths, B. J. Nathan, Evans, Peter J. and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2006. Potent CYP19 (Aromatase) 1-[(Benzofuran-2-yl)(phenylmethyl)pyridine, -imidazole, and -triazole Inhibitors:  Synthesis and Biological Evaluation. Journal of Medicinal Chemistry 49 (3) , pp. 1016-1022. 10.1021/jm0508282

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Abstract

The synthesis of a series of novel 1-[(benzofuran-2-yl)phenylmethyl]-pyridine, -imidazole, and -triazole derivatives is described. All the compounds were evaluated in vitro for inhibitory activity against aromatase (P450AROM, CYP19), using human placental microsomes. The 6-methoxy- and 6-hydroxy-substituted benzofuran derivatives were shown to be potent CYP19 inhibitors (IC50 = 0.01−1.46 μM) with activity greater than that observed for the unsubstituted parent compounds and inhibitory activity comparable with or greater than the reference compound arimidex (IC50 = 0.6 μM). Six of the benzofuran derivatives were subjected to in vitro cytotoxicity assays, using rat liver hepatocytes with cytotoxicity determined from alteration in cell morphology and lactate dehydrogenase enzyme retention over a period of 24 h, and selectivity (CYP17, 17β-HSD types 1 and 3, CYP24, and CYP26) determination; negligible inhibitory activity was observed, suggesting a good selectivity for CYP19. The pyridine benzofuran 4a containing the 4-fluorophenyl group was the most promising (IC50 = 44 nM; LC50 >100 μM) compared with arimidex (IC50 = 600 nM; LC50 > 200 μM).

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:	17 Oct 2022 08:45
URI:	https://orca.cardiff.ac.uk/id/eprint/949

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