Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science.

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.

17ß-Hydroxysteroid Dehydrogenase Type 1 Inhibition: A Potential Treatment Option for Non-Small Cell Lung Cancer.

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 17ß-hydroxysteroid dehydrogenase type 1 (17ß-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 17ß-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 17ß-HSD2 was investigated, revealing a rational approach for the design of selective inhibitors. 17ß-HSD1 and 1 hold promise in fighting NSCLC.

Persulfate Reaction in a Hair-Bleaching Formula: Unveiling the Unconventional Reactivity of 1,13-Diamino-4,7,10-Trioxatridecane.

The stability and unconventional reactivity of 1,13-diamino-4,7,10-trioxatridecane in the presence of NH3, H2O2, and (NH4)2S2O8 are described. The ether-diamine is an ingredient marketed to hair salons and consumers for so-called "plex" services to compensate for hair damage during bleaching. The main reaction product identified is an unexpected azanyl ester derivative. This is considered relevant for the safety evaluation when used in cosmetic products. The mechanism of reaction was explored through DFT calculations. This study represents the first attempt to assess the stability of a plex active in an oxidative environment.

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

17ß-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. 17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) catalyses the last step of E2 biosynthesis and is thus a promising target for the treatment of EDD. The previously described bicyclic substituted hydroxyphenylmethanones (BSHs) display high inhibitory potency towards human 17ß-HSD1, but marginal activity towards rodent 17ß-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) 17ß-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 modeling were applied to elucidate the binding mode and interspecies differences in activity. Compound 33 is the most potent inhibitor of both human and rat 17ß-HSD1 up to date (IC50 = 2 nM and 97 nM, respectively).

17ß-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog.

Design and synthesis of a new class of inhibitors for the treatment of osteoporosis and its comparative h17ß-HSD2 and m17ß-HSD2 SAR study are described. 17a is the first compound to show strong inhibition of both h17ß-HSD2 and m17ß-HSD2, intracellular activity, metabolic stability, selectivity toward h17ß-HSD1, m17ß-HSD1 and estrogen receptors α and ß as well as appropriate physicochemical properties for oral bioavailability. These properties make it eligible for pre-clinical animal studies, prior to human studies.

Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17ß-hydroxysteroid dehydrogenase type 2 inhibitors.

17ß-HSD2 is a promising new target for the treatment of osteoporosis. In this paper, a rational strategy to overcome the metabolic liability in the 2,5-thiophene amide class of 17ß-HSD2 inhibitors is described, and the biological activity of the new inhibitors. Applying different strategies, as lowering the cLogP or modifying the structures of the molecules, compounds 27, 31 and 35 with strongly improved metabolic stability were obtained. For understanding biotransformation in the 2,5-thiophene amide class the main metabolic pathways of three properly selected compounds were elucidated.

Novel, potent and selective 17ß-hydroxysteroid dehydrogenase type 2 inhibitors as potential therapeutics for osteoporosis with dual human and mouse activities.

17ß-Hydroxysteroid dehydrogenase type 2 (17ß-HSD2) is responsible for the oxidation of the highly active estradiol (E2) and testosterone (T) into the less potent estrone (E1) and Δ(4)-androstene-3,17-dione (Δ(4)-AD), respectively. As 17ß-HSD2 is present in bones and as estradiol and testosterone are able to induce bone formation and repress bone resorption, inhibition of this enzyme could be a new promising approach for the treatment of osteoporosis. Herein, we describe the design, the synthesis and the biological evaluation of 24 new 17ß-HSD2 inhibitors in the 5-substituted thiophene-2-carboxamide class. Structure-activity and structure-selectivity relationships have been explored by variation of the sulfur atom position in the central core, exchange of the thiophene by a thiazole, substitution of the amide group with a larger moiety, exchange of the N-methylamide group with bioisosteres like N-methylsulfonamide, N-methylthioamide and ketone, and substitutions at positions 2 and 3 of the thiophene core with alkyl and phenyl groups leading to 2,3,5-trisubstituted thiophene derivatives. The compounds were evaluated on human and mouse enzymes. From this study, a novel highly potent and selective compound in both human and mouse 17ß-HSD2 enzymes was identified, compound 21 (IC50(h17ß-HSD2) = 235 nM, selectivity factor toward h17ß-HSD1 = 95, IC50 (m17ß-HSD2) = 54 nM). This new compound 21 could be used for an in vivo proof of principle to demonstrate the true therapeutic efficacy of 17ß-HSD2 inhibitors in osteoporosis. New structural insights into the active sites of the human and mouse enzymes were gained.

Discovery of a new class of bicyclic substituted hydroxyphenylmethanones as 17ß-hydroxysteroid dehydrogenase type 2 (17ß-HSD2) inhibitors for the treatment of osteoporosis.

E2 deficiency in elderly people has directly an effect on the skeleton and can lead to osteoporosis. As 17ß-hydroxysteroid dehydrogenase type 2 (17ß-HSD2) catalyses the conversion between active 17ß-hydroxysteroid estradiol (E2) and testosterone (T) into their less active 17-ketosteroid and has been found in bones, 17ß-HSD2 inhibitor may provide a new approach in the onset of osteoporosis. Bicyclic substituted hydroxyphenylmethanone derivatives were synthesised as steroidomimetics of the substrate E2 and were evaluated for their 17ß-HSD2 inhibition and their selectivity toward 17ß-HSD1, catalysing the reverse reaction the conversion of estrone (E1) into E2. Highly selective compounds (11, 12, 14, 21 and 22) have been identified, the most promising one (12) showing an IC(50) value in the low nanomolar range (101 nM) and a selectivity factor of 13 toward 17ß-HSD1. These results make compound 12 an interesting candidate for further biological evaluation.