Bicyclic Derivatives of the Potent Dual Aromatase–Steroid Sulfatase Inhibitor 2‐Bromo‐4‐{[(4‐cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenylsulfamate: Synthesis,SAR, Crystal Structure,and in vitro and in vivo Activities |
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Authors: | Paul?M Wood Dr L?W Lawrence Woo Dr Jean‐Robert Labrosse Dr Mark?P Thomas Dr Mary?F Mahon Dr Surinder?K Chander Dr Atul Purohit Dr Michael?J Reed Prof Barry?V?L Potter Prof |
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Affiliation: | 1. Department of Pharmacy and Pharmacology and Sterix Ltd. University of Bath, Claverton Down, Bath BA2?7AY (UK), Fax: (+44)?1225‐386‐114;2. X‐Ray Crystallographic Suite, Department of Chemistry, University of Bath, Claverton Down, Bath, BA2?7AY (UK);3. Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College London, Faculty of Medicine, St. Mary's Hospital, London, W2?1NY (UK) |
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Abstract: | The design and synthesis of a series of bicyclic ring containing dual aromatase–sulfatase inhibitors (DASIs) based on the aromatase inhibitor (AI) 4‐(4‐bromobenzyl)(4H‐1,2,4‐triazol‐4‐yl)amino]benzonitrile are reported. Biological evaluation with JEG‐3 cells revealed structure–activity relationships. The X‐ray crystal structure of sulfamate 23 was determined, and selected compounds were docked into the aromatase and steroid sulfatase (STS) crystal structures. In the sulfamate‐containing series, compounds containing a naphthalene ring are both the most potent AI ( 39 , IC50 AROM=0.25 nM ) and the best STS inhibitor ( 31 , IC50 STS=26 nM ). The most promising DASI is 39 (IC50 AROM=0.25 nM , IC50 STS=205 nM ), and this was evaluated orally in vivo at 10 mg kg?1, showing potent inhibition of aromatase (93 %) and STS (93 %) after 3 h. Potent aromatase and STS inhibition can thus be achieved with a DASI containing a bicyclic ring system; development of such a DASI could provide an attractive new option for the treatment of hormone‐dependent breast cancer. |
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Keywords: | aromatase breast cancer dual inhibitors endocrine therapy sulfatase |
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