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Discovery of a non-estrogenic irreversible inhibitor of 17{Beta}-hydroxysteroid dehydrogenase type 1 from 3-substituted-16{Beta}-(m-carbamoylbenzyl)-estradiol derivatives

Discovery of a non-estrogenic irreversible inhibitor of 17{Beta}-hydroxysteroid dehydrogenase type 1 from 3-substituted-16{Beta}-(m-carbamoylbenzyl)-estradiol derivatives. Global Medical Discovery

Journal Reference

Maltais R, Ayan D, Trottier A, Barbeau X, Lagüe P, Bouchard JE, Poirier D.

J Med Chem. 2014 Jan 9;57(1):204-22.

Laboratory of Medicinal Chemistry, Oncology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4-42) and Faculty of Medicine, Laval University , Québec City, Québec G1V 4G2, Canada.

Abstract

17{Beta}-Hydroxysteroid dehydrogenase type 1 (17{Beta}-HSD1) is thought to play a pivotal role in the progression of estrogen-sensitive breast cancer by transforming estrone (E1) into estradiol (E2). We designed three successive series of E2-derivatives at position C3 of the potent inhibitor 16{Beta}-(m-carbamoylbenzyl)-E2 to remove its unwanted estrogenic activity. We report the chemical synthesis and characterization of 20 new E2-derivatives, their evaluation as 17{Beta}-HSD1 inhibitors, and their proliferative (estrogenic) activity on estrogen-sensitive cells. The structure-activity relationship study provided a new potent and steroidal nonestrogenic inhibitor of 17{Beta}-HSD1 named 3-{[(16{Beta},17{Beta})-3-(2-bromoethyl)-17-hydroxyestra-1(10),2,4-trien-16-yl]methyl}benzamide (23b). In fact, this compound inhibited the transformation of E1 into E2 by 17{Beta}-HSD1 in T-47D cells (IC50 = 83 nM), did not inhibit 17{Beta}-HSD2, 17{Beta}-HSD7, 17{Beta}-HSD12, and CYP3A4, and did not stimulate the proliferation of estrogen-sensitive MCF-7 cells. We also discussed the results of kinetic and molecular modeling (docking) experiments, suggesting that compound 23b is a competitive and irreversible inhibitor of 17{Beta}-HSD1.

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