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In Vivo Inhibition of Estrone Sulfatase Activity and Growth of Nitrosomethylurea-induced Mammary Tumors by 667 COUMATE¹

Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College School of Medicine, St. Mary’s Hospital, London W2 1NY, United Kingdom [A. P., M. J. R.], and Wolfson Laboratory of Medicinal Chemistry and Sterix Ltd., Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom [L. W. L. W., B. V. L. P.]

The development of potent steroid sulfatase inhibitors is an important new therapeutic strategy for the treatment of postmenopausal women with breast cancer. A series of tricyclic coumarin sulfamates were synthesized, and their inhibitory properties were examined in vitro and in vivo. In a placental microsomal assay system, 667 COUMATE emerged as the most potent inhibitor with an IC₅₀ of 8 nM. Administration of a single dose (10 mg/kg, p.o.) of 667 COUMATE inhibited rat liver estrone sulfatase activity by 93%. 667 COUMATE was devoid of estrogenicity, as indicated by its failure to stimulate the growth of uteri in ovariectomized rats. In vivo, estrone sulfate-stimulated growth of uteri in ovariectomized rats was inhibited by 667 COUMATE. Using the nitrosomethylurea-induced mammary tumor model, we found that 667 COUMATE caused regression of estrone sulfate-stimulated tumor growth in a dose-dependent manner. The identification of 667 COUMATE as a potent steroid sulfatase inhibitor will enable the therapeutic potential of this type of therapy to be evaluated.

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