A letrozole-based dual aromatase-sulphatase inhibitor with in vivo activity.
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.
Wood
Paul M
PM
Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd, University of Bath, Claverton Down, Bath, England BA2 7AY, UK.
Woo
L W Lawrence
LW
Humphreys
Anna
A
Chander
Surinder K
SK
Purohit
Atul
A
Reed
Michael J
MJ
Potter
Barry V L
BV
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*
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D009570:Nitriles; D014230:Triazoles; C096486:YM 511; D000077289:Letrozole; D013429:Sulfatases