Pyridine based dual binding site aromatase (CYP19A1) inhibitors

Ahmed G Eissa, Lauren Powell, Julia Gee, Paul Foster, Claire Simons*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Downloads (Pure)


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.
Original languageEnglish
Number of pages11
JournalRSC Medicinal Chemistry
Early online date3 Jan 2023
Publication statusE-pub ahead of print - 3 Jan 2023


Dive into the research topics of 'Pyridine based dual binding site aromatase (CYP19A1) inhibitors'. Together they form a unique fingerprint.

Cite this