Recent advances in the development of steroid sulphatase inhibitors

Inhibition of steroid sulphatase is now an important target for the develop ment of new drugs for the treatment of women with endocrine-dependent breas t rumours. The first potent sulphatase inhibitor identified, oestrone-3-O-s ulphamale (EMATE) proved, unexpectedly, to be oestrogenic. A number of stra tegies have therefore been adopted to design and synthesize a nonoestrogeni c inhibitor. For this, a number of modifications have been made to the A an d D rings of the oestrone nucleus. 2 Methoxyoestrone-3-O-sulphamale, while having similar in vitro and in vivo sulphatase inhibitory potency to that o f EMATE, was devoid of oestrogenic activity when tested at 2 mg/kg in an ov ariectomised rat uterine weight gain assay. 17-Deoxyoestrone-3-O-sulphamate was also a potent steroid sulphatase inhibitor and while it was devoid of oestrogenic activity when tested at 0.1 mg/kg, did stimulate uterine growth at 1.0 mg/kg. As an alternative approach to the use of steroid-based inhib itors a number of single ring, bicyclic non-fused ring, and two fused ring sulphamate analogues were designed, synthesized and tested for their abilit y to inhibit steroid sulphatase activity. In general, although the single r ing and bicyclic non-fused ring sulphamate analogues could inhibit sulphata se activity, they were considerably less potent than EMATE. The mono- and b is-sulphamate derivatives of 5,7-dihydroxyisoflavone were relatively potent , inhibiting in vivo steroid sulphatase activity by 62 and 81% respectively at a single oral dose of 10 mg/kg. A study of the structure-activity relat ionship of a series of coumarin-based sulphamates has led to the developmen t of a number of potent non-steroidal inhibitors, one of which has a simila r potency to that of EMATE. The identification of potent steroid- and non-s teroid-based sulphatase inhibitors will enable the therapeutic value of thi s therapy to be examined in the near future. (C) 1999 Elsevier Science Ltd. All rights reserved.