Bubert, Christian published the artcileSynthesis 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, Computed Properties of 33697-81-3, the publication is ChemMedChem (2008), 3(11), 1708-1730, database is CAplus and MEDLINE.
4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (I) 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 synthesized and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors II (n = 2, R1 = R2 = H) and III, and DASI II (n = 5, R1 = H, R2 = SO2NH2) were determined Nearly all derivatives show improved in vitro aromatase inhibition over I but decreased STS inhibition. The best aromatase inhibitor is II (n = 2, R1 = Cl, R2 = H) (IC50 = 0.26 nM) and the best DASI is II (n = 2, R1 = Cl, R2 = SO2NH2) (IC50aromatase = 0.45 nM, IC50STS = 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 II (R2 = SO2NH2: n = 2, R1 = H; n = 2, R1 = Cl; n = 3, R1 = H, n = 4, R1 = H) were studied in vivo (10 mg kg-1, single, p.o.). The most potent DASI is II (n = 2, R1 = H, R2 = SO2NH2), which inhibited PMSG-induced plasma estradiol levels by 92% and liver STS activity by 98% 3h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers.
ChemMedChem published new progress about 33697-81-3. 33697-81-3 belongs to chlorides-buliding-blocks, auxiliary class Chloride,Carboxylic acid,Benzene,Phenol, name is 3-Chloro-4-hydroxyphenylacetic acid, and the molecular formula is C8H7ClO3, Computed Properties of 33697-81-3.
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