N-acyl arylsulfonamides as novel, reversible inhibitors of human steroid sulfatase

Abstract Steroid sulfatase (STS) is an attractive target for a range of oestrogen- and androgen-dependent diseases. In search of novel chemotypes of STS inhibitors, we had previously identified nortropinyl–arylsulfonylureas 1 ; however, while these compounds were good inhibitors of purified STS (lowest K i  = 76 nM), they showed only weak inhibition of STS activity in cells (lowest IC 50 around 2 μM). Extended structure–activity relationship studies involving modification of the phenylacetyl side chain and replacement of the nortropine element by simpler scaffolds led to the discovery of N -acyl arylsulfonamides, more specifically N -(Boc-piperidine-4-carbonyl)-benzenesulfonamides, as STS inhibitors, some of which exhibit improved cellular potency (best IC 50  = 270 nM).