title: A letrozole-based dual aromatase-sulphatase inhibitor with in vivo activity.
abstract: The role of aromatase inhibitors in the treatment of hormone-dependent breast cancer is well established. However, it is now recognised that steroid sulphatase (STS) inhibitors represent a new form of endocrine therapy. To explore the potential advantage of dual inhibition by a single agent, we recently developed a series of dual aromatase-sulphatase inhibitors (DASIs) based on the aromatase inhibitor YM511. We report here a new structural class of DASI obtained by obtained introducing the pharmacophore for STS inhibition, i.e. a phenol sulphamate ester into another established aromatase inhibitor letrozole. Hence, the bis-sulphamate 9 was synthesised which exhibited IC(50) values of 3044 nM for aromatase and >10 microM for STS in JEG-3 cells. However, at a single oral dose of 10mg/kg, 9 inhibited aromatase and rat liver STS by 60% and 88%, respectively, 24h after administration. A proposed metabolite of 9, carbinol 10, was synthesised. Despite also showing weak STS inhibition in JEG-3 cells, 10 inhibited rat liver STS activity to the same extent as 9 at a single oral dose of 10mg/kg. Thus, the concept of a letrozole-based DASI has been validated and could be further developed and modified for therapeutic exploitation.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd, University of Bath, Claverton Down, Bath, England BA2 7AY, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Wood
authors.forename: L W Lawrence
authors.initials: LW
authors.lastname: Woo
authors.forename: Anna
authors.initials: A
authors.lastname: Humphreys
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Chander
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D047072:Aromatase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007202:Indicators and Reagents; D000077289:Letrozole; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology*; D013429:Sulfatases / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D009570:Nitriles; D014230:Triazoles; C096486:YM 511; D000077289:Letrozole; D013429:Sulfatases