2-(1-adamantyl)-4-(thio)chromenone-6-carboxylic acids: potent reversible inhibitors of human steroid sulfatase.

Steroid sulfatase (STS) is an attractive target for the potential therapy of a number of estrogen- and androgen-dependent disorders. Most potent STS inhibitors known so far act as irreversible enzyme blockers and feature an aryl sulfamate moiety; even minor modifications at the sulfamate group result in drastically decreased activity. On the basis of a recently reported subclass of highly potent STS inhibitors, i.e., chromenone sulfamates, we now extended the investigation of structure-activity relationships to hitherto unstudied sulfamate replacements. Thereby, we discovered 2-(1-adamantyl)-4-(thio)chromenone-6-carboxylic acids (5d and 5j) as potent, reversible inhibitors of STS. In a cell-free system using purified human STS, both new inhibitors show similar Ki values (0.50 microM and 0.53 microM, respectively). However, the thio analogue 5j is superior to 5d (IC50 = 0.18 microM versus 9.4 microM) in a cellular assay system using CHO cells overexpressing STS. Compound 5j is an example of a reversible STS inhibitor with potent activity toward the target enzyme in a cellular test system. Moreover, 5d,j are stable and have no estrogenic potential.

Nortropinyl-arylsulfonylureas as novel, reversible inhibitors of human steroid sulfatase.

Steroid sulfatase (STS) has emerged as an attractive target for a range of estrogen- and androgen-dependent diseases. Searching for novel chemotypes as STS inhibitors, we identified nortropinyl-arylsulfonylurea 3 as a hit from high-throughput screening. A series of analogues was prepared in order to explore the essential structural elements for STS inhibition, and first structure-activity relationships were established. Mechanistic investigations revealed that the compounds are reversible, competitive inhibitors of STS.