Synthesis of aromatase inhibitors and dual aromatase-sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, crystal structures, in vitro and in vivo activities

C. Bubert, L.W.L. Woo, O.B. Sutcliffe, M.F. Mahon, S.K. Chander, A. Purohit, M.J. Reed, B.V.L. Potter

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42 d and 60, and DASI 43 h were determined. Nearly all derivatives show improved in vitro aromatase inhibition over 6 a but decreased STS inhibition. The best aromatase inhibitor is 42 e (IC50=0.26 nM) and the best DASI is 43 e (IC50 aromatase=0.45 nM, IC50 STS=1200 nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43 d-f were studied in vivo (10 mg kg-1, single, p.o.). The most potent DASI is 43 e, which inhibited PMSG-induced plasma estradiol levels by 92 % and liver STS activity by 98 % 3 h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers.
Original languageEnglish
Pages (from-to)1708-1730
Number of pages22
JournalChemMedChem
Volume3
Issue number11
DOIs
Publication statusPublished - Sep 2008

Keywords

  • aromatase inhibitors
  • breast cancer
  • dual aromatase-sulfatase inhibitors
  • endocrine therapy
  • sulfatase inhibitors
  • pharmacology

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