title: Dual aromatase-steroid sulfatase inhibitors.
abstract: By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology and Sterix Limited, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: L W Lawrence
authors.initials: LW
authors.lastname: Woo
authors.forename: Christian
authors.initials: C
authors.lastname: Bubert
authors.forename: Oliver B
authors.initials: OB
authors.lastname: Sutcliffe
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Chander
authors.forename: Mary F
authors.initials: MF
authors.lastname: Mahon
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: D000818:Animals; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D013449:Sulfonamides; D014230:Triazoles; C523411:sulfamic acid 2-bromo-4-(((4-cyanophenyl)(1,2,4)triazol-4-ylamino)methyl)phenyl ester; C523412:sulfamic acid 5-(((4-cyanophenyl)(1,2,4)triazol-4-ylamino)methyl)-2-fluorophenyl ester; D043266:Steryl-Sulfatase