Development of potential preclinical candidates with promising in vitro ADME profile for the inhibition of type 1 and type 2 17β-Hydroxysteroid dehydrogenases: Design, synthesis, and biological evaluation.

Autor: Abdelsamie AS; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Department of Drug Design and Optimization, Campus Building E8.1, 66123, Saarbrücken, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Saarbrücken, Germany; Chemistry of Natural and Microbial Products Department, National Research Centre, Dokki, 12622, Cairo, Egypt. Electronic address: Ahmed-Saad-Abdelsamie.Ahmed@helmholtz-hips.de., Salah M; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, 66123, Saarbrücken, Germany., Siebenbürger L; PharmBioTec GmbH, Science Park 1, 66123, Saarbrücken, Germany., Hamed MM; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Department of Drug Design and Optimization, Campus Building E8.1, 66123, Saarbrücken, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Saarbrücken, Germany., Börger C; PharmBioTec GmbH, Science Park 1, 66123, Saarbrücken, Germany., van Koppen CJ; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, 66123, Saarbrücken, Germany; ElexoPharm GmbH, Im Stadtwald, Building A1.2, 66123, Saarbrücken, Germany., Frotscher M; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, 66123, Saarbrücken, Germany., Hartmann RW; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Department of Drug Design and Optimization, Campus Building E8.1, 66123, Saarbrücken, Germany; Department of Pharmaceutical and Medicinal Chemistry, Saarland University, 66123, Saarbrücken, Germany.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2019 Sep 15; Vol. 178, pp. 93-107. Date of Electronic Publication: 2019 May 31.
DOI: 10.1016/j.ejmech.2019.05.084
Abstrakt: Estrogens are the major female sex steroid hormones, estradiol (E2) being the most potent form in humans. Disturbing the balance between E2 and its weakly active oxidized form estrone (E1) leads to diverse types of estrogen-dependent diseases such as endometriosis or osteoporosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of E2 by reduction of E1 while the type 2 enzyme catalyzes the reverse reaction. Thus, 17β-HSD1 and 17β-HSD2 are attractive targets for treatment of estrogen-dependent diseases. Recently, we reported the first proof-of-principle study of a 17β-HSD2 inhibitor in a bone fracture mouse model, using subcutaneous administration. In the present study, our aim was to improve the in vitro ADME profile of the most potent 17β-HSD1 and 17β-HSD2 inhibitors described so far. The optimized compounds show strong and selective inhibition of both the human enzymes and their murine orthologs. In addition, they display good metabolic stability in human liver microsomes (S9 fraction), low in vitro cytotoxicity as well as better aqueous solubility and physicochemical properties compared to the lead compounds. These achievements make the compounds eligible for testing in preclinical in vivo animal model studies on the effects of inhibition of 17β-HSD1 and 17β-HSD2.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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