Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

Abstract

CitationTowards the evaluation in an animal disease model: Fluorinated 17-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme. Abstract 17β-Estradiol (E2), the most potent human estrogen, is known to be involved in the etiology of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step of E2 biosynthesis and is thus a promising target for the treatment of EDD. The previously described bicyclic substituted hydroxyphenyl methanones (BSHs) display high inhibitory potency towards human 17β-HSD1, but marginal activity towards rodent 17β-HSD1, precluding a proof of principle study in an animal endometriosis model. The aim of this work was to perform structural optimizations in the BSHs class to enhance inhibitory activity against rodent (mouse and rat) 17β-HSD1 while maintaining activity against the human enzyme. The introduction of fluorine atoms on the benzoyl moiety resulted in compounds with the desired properties. Molecular docking and homology modelling were applied to elucidate the binding mode and interspecies differences in activity. Compound 33 is the most potent inhibitor of both human and rat 17β-HSD1 up to date (IC 50 = 2 nM and 97 nM, respectively).Keywords: 17β-Hydroxysteroid dehydrogenase type 1, Interspecies differences, Estrogendependent diseases, Estrogen mimetics, Non-steroidal inhibitors

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

“…As a consequence, one of its proposed therapeutic approaches is the reduction of E2 synthesis by the inhibition of 17β-HSD1 [86]. Several steroidal and non-steroidal 17β-HSD1 inhibitors are under pharmacological investigation targeting endometriosis [87][88][89], and an effort has been made to develop a reliable murine animal model of the disease as well [90].…”

Targeted Endocrine Therapy: Design, Synthesis, and Proof-of-Principle of 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors in Bone Fracture Healing

“…As bicyclic substituted hydroxyphenylmethanones (BSHs) bearing a sulfonamide moiety were originally designed as inhibitors of human 17β-HSD1, most members show selectivity toward 17β-HSD1 over 17β-HSD2. 18 In addition, BSHs display low metabolic stability, precluding their use in an in vivo proof-of-principle study. Thus, a rational two-stage drug design strategy focusing on rings A and D (Charts 1 and 2, see also Supporting Information for details) was applied that, on the one hand, aimed at improving the metabolic stability and, on the other, at enhancing the potency and selectivity for human and murine 17β-HSD2 (h + m17β-HSD2), resulting in a small library of 16 compounds.…”

“…Only such groups were selected to be introduced that were likely to maintain potency toward both human and mouse 17β-HSD2. 18 We aimed for a slight (three-to  fourfold) selectivity over the h17β-HSD1 enzyme (Chart 2, 9− 16). On the one hand, a highly selective 17β-HSD2 inhibitor would induce an undesirable increase in intracellular E2 in tissues that express similar levels of 17β-HSD2 and 17β-HSD1 and prone to E2-dependent proliferation (i.e., breast 20,21 and endometrium 22 ), whereas on the other hand, a nonselective 17β-HSD2/1 inhibitor would likely affect the role of 17β-HSD1 in regulating the endometrium cyclicity in women of childbearing age.…”

“…As bicyclic substituted hydroxyphenylmethanones (BSHs) bearing a sulfonamide moiety were originally designed as inhibitors of human 17β-HSD1, most members show selectivity toward 17β-HSD1 over 17β-HSD2 . In addition, BSHs display low metabolic stability, precluding their use in an in vivo proof-of-principle study.…”

Virtual screening applications in short-chain dehydrogenase/reductase research

“…In this regard, an initial enzymatic assay including only the orthologue of the subsequently used animal model species would miss potential inhibitors for human applications. Abdelsamie et al performed structural optimization studies to enhance the potency of a 17β-HSD1 inhibitor against the rodent enzyme and performed docking and homology modeling applications to elucidate the interspecies differences [210]. The observed species-specific protein-ligand interactions might offer valuable information for the design of new inhibitors.…”