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Pyridine based dual binding site aromatase (CYP19A1) inhibitors

Eissa, Ahmed G., Powell, Lauren E., Gee, Julia ORCID:, Foster, Paul A. and Simons, Claire ORCID: 2023. Pyridine based dual binding site aromatase (CYP19A1) inhibitors. RSC Medicinal Chemistry 14 (2) , pp. 356-366. 10.1039/d2md00352j

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Aromatase (CYP19A1) inhibitors are the mainstay therapeutics for the treatment of hormone dependant breast cancer, which accounts for approximately 70% of all breast cancer cases. However, increased resistance to the clinically used aromatase inhibitors, including letrozole and anastrazole, and off target effects, necessitates the development of aromatase inhibitors with improved drug profiles. The development of extended 4th generation pyridine based aromatase inhibitors with dual binding (haem and access channel) is therefore of interest and here we describe the design, synthesis and computational studies. Cytotoxicity and selectivity studies identified the pyridine derivative (4-bromophenyl)(6-(but-2-yn-1-yloxy)benzofuran-2-yl)(pyridin-3-yl)methanol (10c) as optimal with CYP19A1 IC50 0.83 nM (c.f. letrozole IC50 0.70 nM), and an excellent cytotoxicity and selectivity profile. Interestingly, computational studies for the 6-O-butynyloxy (10) and 6-O-pentynyloxy (11) derivatives identified an alternative access channel lined by Phe221, Trp224, Gln225 and Leu477, providing further insight into the potential binding mode and interactions of the non-steroidal aromatase inhibitors.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Additional Information: License information from Publisher: LICENSE 1: URL:, Start Date: 2023-01-03
Publisher: Royal Society of Chemistry
ISSN: 2632-8682
Date of First Compliant Deposit: 19 January 2023
Date of Acceptance: 19 December 2022
Last Modified: 03 May 2023 08:38

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