Synthesis of aromatase inhibitors and dual aromatase steroid 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.
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 (IC(50)=0.26 nM) and the best DASI is 43 e (IC(50 aromatase)=0.45 nM, IC(50 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.
Bubert
Christian
C
Department of Pharmacy and Pharmacology & Sterix Ltd. University of Bath, Claverton Down, Bath, UK.
Woo
L W Lawrence
LW
Sutcliffe
Oliver B
OB
Mahon
Mary F
MF
Chander
Surinder K
SK
Purohit
Atul
A
Reed
Michael J
MJ
Potter
Barry V L
BV
D020816:Amino Acid Motifs; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004958:Estradiol / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D009570:Nitriles / Q000737:chemistry*; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry*
C540262:4-(4H-1,2,4-triazol-4-ylamino)benzonitrile; D047072:Aromatase Inhibitors; D009570:Nitriles; D013449:Sulfonamides; D014230:Triazoles; D004958:Estradiol; C014356:benzonitrile; D001141:Aromatase; D043266:Steryl-Sulfatase