Various derivatives of the tetrahydroisoquinoline core were designed as non-steroidal dual-action inhibitors of steroid sulfatase (STS). Sulfamate derivatives and their corresponding phenol derivatives were both synthesized by parallel solid-phase chemistry. The sulfamate compounds were tested for their ability to inhibit STS activity, whereas the phenol compounds were tested for their ability or non-ability to induce the proliferation of estrogen-dependent MCF-7 and Saos-2 cells. Interestingly, many sulfamate derivatives showed good inhibitory activity toward the enzyme (80–90% of inhibition at 0.1 mM), whereas four phenol derivatives did not present unwanted estrogenic activity on MCF-7 cells but induced a proliferation of Saos-2 cells, thus suggesting a selective-estrogen receptor modulator potential.