Design and synthesis of a new class of inhibitors for the treatment of osteoporosis and its comparative h17β-HSD2 and m17β-HSD2 SAR study are described. 17a is the first compound to show strong inhibition of both h17β-HSD2 and m17β-HSD2, intracellular activity, metabolic stability, selectivity toward h17β-HSD1, m17β-HSD1 and estrogen receptors α and β as well as appropriate physicochemical properties for oral bioavailability. These properties make it eligible for pre-clinical animal studies, prior to human studies.
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
Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor BI-3231. Through high-throughput screening (HTS), using estradiol as substrate, compound 1 was identified and selected for subsequent optimization resulting in compound 45 (BI-3231). In addition to the characterization of compound 45 for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD + dependency was investigated. To support Open Science, the chemical HSD17B13 probe BI-3231 will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.
In the face of the clinical challenge
posed by non-small cell lung
cancer (NSCLC), the present need for new therapeutic approaches is
genuine. Up to now, no proof existed that 17β-hydroxysteroid
dehydrogenase type 1 (17β-HSD1) is a viable target for treating
this disease. Synthesis of a rationally designed library of 2,5-disubstituted
furan derivatives followed by biological screening led to the discovery
of 17β-HSD1 inhibitor 1, capable of fully inhibiting
human NSCLC Calu-1 cell proliferation. Its pharmacological profile
renders it eligible for further in vivo studies.
The very high selectivity of 1 over 17β-HSD2 was
investigated, revealing a rational approach for the design of selective
inhibitors. 17β-HSD1 and 1 hold promise in fighting
NSCLC.
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