Inhibitory effects of parabens on human and rat 17ß-hydroxysteroid dehydrogenase 1: Mechanisms of action and impact on hormone synthesis.

Parabens are commonly used preservatives in cosmetics, food, and pharmaceutical products. The objective of this study was to examine the effect of nine parabens on human and rat 17ß-hydroxysteroid dehydrogenase 1 (17ß-HSD1) in human placental and rat ovarian cytosols, as well as on estradiol synthesis in BeWo cells. The results showed that the IC50 values for these compounds varied from methylparaben with the weakest inhibition (106.42 µM) to hexylparaben with the strongest inhibition (2.05 µM) on human 17ß-HSD1. Mode action analysis revealed that these compounds acted as mixed inhibitors. For rats, the IC50 values ranged from the weakest inhibition for methylparaben (no inhibition at 100 µM) to the most potent inhibition for hexylparaben (0.87 µM), and they functioned as mixed inhibitors. Docking analysis indicated that parabens bind to the region bridging the NADPH and steroid binding sites of human 17ß-HSD1 and the NADPH binding site of rat 17ß-HSD1. Bivariate correlation analysis demonstrated negative correlations between LogP, molecular weight, heavy atoms, and apolar desolvation energy, and the IC50 values of these compounds. In conclusion, this study identified the inhibitory effects of parabens and their binding mechanisms on human and rat 17ß-HSD1, as well as their impact on hormone synthesis.

Pharmacological inhibition of 17ß-hydroxysteroid dehydrogenase impairs human endometrial cancer growth in an orthotopic xenograft mouse model.

Endometrial cancer (EC) is the most common gynaecological tumor in developed countries and its incidence is increasing. Approximately 80% of newly diagnosed EC cases are estrogen-dependent. Type 1 17ß-hydroxysteroid dehydrogenase (17ß-HSD-1) is the enzyme that catalyzes the final step in estrogen biosynthesis by reducing the weak estrogen estrone (E1) to the potent estrogen 17ß-estradiol (E2), and previous studies showed that this enzyme is implicated in the intratumoral E2 generation in EC. In the present study we employed a recently developed orthotopic and estrogen-dependent xenograft mouse model of EC to show that pharmacological inhibition of the 17ß-HSD-1 enzyme inhibits disease development. Tumors were induced in one uterine horn of athymic nude mice by intrauterine injection of the well-differentiated human endometrial adenocarcinoma Ishikawa cell line, modified to express human 17ß-HSD-1 in levels comparable to EC, and the luciferase and green fluorescent protein reporter genes. Controlled estrogen exposure in ovariectomized mice was achieved using subcutaneous MedRod implants that released either the low active estrone (E1) precursor or vehicle. A subgroup of E1 supplemented mice received daily oral gavage of FP4643, a well-characterized 17ß-HSD-1 inhibitor. Bioluminescence imaging (BLI) was used to measure tumor growth non-invasively. At sacrifice, mice receiving E1 and treated with the FP4643 inhibitor showed a significant reduction in tumor growth by approximately 65% compared to mice receiving E1. Tumors exhibited metastatic spread to the peritoneum, to the lymphovascular space (LVI), and to the thoracic cavity. Metastatic spread and LVI invasion were both significantly reduced in the inhibitor-treated group. Transcriptional profiling of tumors indicated that FP4643 treatment reduced the oncogenic potential at the mRNA level. In conclusion, we show that 17ß-HSD-1 inhibition represents a promising novel endocrine treatment for EC.

A Hybrid In Silico/In Vitro Target Fishing Study to Mine Novel Targets of Urolithin A and B: A Step Towards a Better Comprehension of Their Estrogenicity.

SCOPE: Urolithin A and B are gut metabolites of ellagic acid and ellagitannins associated with many beneficial effects. Evidence in vitro pointed to their potential as estrogenic modulators. However, both molecular mechanisms and biological targets involved in such activity are still poorly characterized, preventing a comprehensive understanding of their bioactivity in living organisms. This study aimed at rationally identifying novel biological targets underlying the estrogenic-modulatory activity of urolithins. METHODS AND RESULTS: The work relies on an in silico/in vitro target fishing study coupling molecular modeling with biochemical and cell-based assays. Estrogen sulfotransferase and 17ß-hydroxysteroid dehydrogenase are identified as potentially subject to inhibition by the investigated urolithins. The inhibition of the latter undergoes experimental confirmation either in a cell-free or cell-based assay, validating computational outcomes. CONCLUSIONS: The work describes target fishing as an effective tool to identify unexpected targets of food bioactives detailing the interaction at a molecular level. Specifically, it described, for the first time, 17ß-hydroxysteroid dehydrogenase as a target of urolithins and highlighted the need of further investigations to widen the understanding of urolithins as estrogen modulators in living organisms.

Design, Synthesis, and Biological Characterization of Orally Active 17ß-Hydroxysteroid Dehydrogenase Type 2 Inhibitors Targeting the Prevention of Osteoporosis.

Osteoporosis is predominantly treated with drugs that inhibit further bone resorption due to estrogen deficiency. Yet, osteoporosis drugs that not only inhibit bone resorption but also stimulate bone formation, such as potentially inhibitors of 17ß-hydroxysteroid dehydrogenase type 2 (17ß-HSD2), may be more efficacious in the treatment of osteoporosis. Blockade of 17ß-HSD2 is thought to increase intracellular estradiol and testosterone in bone, thereby inhibiting bone resorption by osteoclasts and stimulating bone formation by osteoblasts, respectively. We here describe the design, synthesis, and biological characterization of a novel bicyclic-substituted hydroxyphenylmethanone 17ß-HSD2 inhibitor (compound 24). Compound 24 is a nanomolar potent inhibitor of human 17ß-HSD2 (IC50 of 6.1 nM) and rodent 17ß-HSD2 with low in vitro cellular toxicity, devoid of detectable estrogen receptor α affinity, displays high aqueous solubility and in vitro metabolic stability, and has an excellent oral pharmacokinetic profile for testing in a rat osteoporosis model. Administration of 24 in a rat osteoporosis model demonstrates its bone-sparing efficacy.

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

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. 17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) catalyzes the biosynthesis of E2 by reduction of E1 while the type 2 enzyme catalyzes the reverse reaction. Thus, 17ß-HSD1 and 17ß-HSD2 are attractive targets for treatment of estrogen-dependent diseases. Recently, we reported the first proof-of-principle study of a 17ß-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 17ß-HSD1 and 17ß-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 17ß-HSD1 and 17ß-HSD2.

siRNA-based breast cancer therapy by suppressing 17ß-hydroxysteroid dehydrogenase type 1 in an optimized xenograft cell and molecular biology model in vivo.

PURPOSE: Hormone-dependent breast cancer is the most common form of breast cancer, and inhibiting 17ß-HSD1 can play an attractive role in decreasing estrogen and cancer cell proliferation. However, the majority of existing inhibitors have been developed from estrogens and inevitably possess residual estrogenicity. siRNA knockdown provides a highly specific way to block a targeted enzyme, being especially useful to avoid estrogenicity. Application of 17ß-HSD1-siRNA in vivo is limited by the establishment of an animal model, as well as the potential nuclease activity in vivo. We tried to reveal the in vivo potential of 17ß-HSD1-siRNA-based breast cancer therapy. MATERIALS AND METHODS: To establish a competent animal model, daily subcutaneous injection of an estrone micellar aqueous solution was adopted to provide the substrate for estradiol biosynthesis. The effects of three different doses of estrone (0.1, 0.5, and 2.5 µg/kg/day) on tumor growth in T47D-17ß-HSD1-inoculated group were investigated and compared with the animals inoculated with wild type T47D cells. To solve in vivo delivery problem of siRNA, "17ß-HSD1-siRNA/LPD", a PEGylated and modified liposome-polycation-DNA nanoparticle containing 17ß-HSD1-siRNA was prepared by the thin film hydration method and postinsertion technology. Finally, "17ß-HSD1-siRNA/LPD" was tested in the optimized model. Tumor growth and 17ß-HSD1 expression were assessed. RESULTS: Comparison with the untreated group revealed significant suppression of tumor growth in "17ß-HSD1-siRNA/LPD"-treated group when HSD17B1 gene expression was knocked down. CONCLUSION: These findings showed promising in vivo assessments of 17ß-HSD1-siRNA candidates. This is the first report of an in vivo application of siRNA for steroid-converting enzymes in a nude mouse model.

Highly Potent 17ß-HSD2 Inhibitors with a Promising Pharmacokinetic Profile for Targeted Osteoporosis Therapy.

Intracellular elevation of E2 levels in bone by inhibition of 17ß hydroxysteroid dehydrogenase type 2 (17ß-HSD2) without affecting systemic E2 levels is an attractive approach for a targeted therapy against osteoporosis, a disease which is characterized by loss of bone mineral density. Previously identified inhibitor A shows high potency on human and mouse 17ß-HSD2, but poor pharmacokinetic properties when applied perorally in mice. A combinatorial chemistry approach was utilized to synthesize truncated derivatives of A, leading to highly potent compounds with activities in the low nanomolar to picomolar range. Compound 33, comparable to A in terms of inhibitor potency against both human and mouse enzymes, displays high in vitro metabolic stability in human and mouse liver S9 fraction as well as low toxicity and moderate hepatic CYP inhibition. Thus, compound 33 showed a highly improved peroral pharmacokinetic profile in comparison to A, making 33 a promising candidate for further development.

Synthesis and structure-activity relationships of 2- and/or 4-halogenated 13ß- and 13α-estrone derivatives as enzyme inhibitors of estrogen biosynthesis.

Ring A halogenated 13α-, 13ß-, and 17-deoxy-13α-estrone derivatives were synthesised with N-halosuccinimides as electrophile triggers. Substitutions occurred at positions C-2 and/or C-4. The potential inhibitory action of the halogenated estrones on human aromatase, steroid sulfatase, or 17ß-hydroxysteroid dehydrogenase 1 activity was investigated via in vitro radiosubstrate incubation. Potent submicromolar or low micromolar inhibitors were identified with occasional dual or multiple inhibitory properties. Valuable structure-activity relationships were established from the comparison of the inhibitory data obtained. Kinetic experiments performed with selected compounds revealed competitive reversible inhibition mechanisms against 17ß-hydroxysteroid dehydrogenase 1 and competitive irreversible manner in the inhibition of the steroid sulfatase enzyme.

Steroid sulfatase inhibition success and limitation in breast cancer clinical assays: An underlying mechanism.

Steroid sulfatase is detectable in most hormone-dependent breast cancers. STX64, an STS inhibitor, induced tumor reduction in animal assay. Despite success in phase І clinical trial, the results of phase II trial were not that significant. Breast Cancer epithelial cells (MCF-7 and T47D) were treated with two STS inhibitors (STX64 and EM1913). Cell proliferation, cell cycle, and the concentrations of estradiol and 5α-dihydrotestosterone were measured to determine the endocrinological mechanism of sulfatase inhibition. Comparisons were made with inhibitions of reductive 17ß-hydroxysteroid dehydrogenases (17ß-HSDs). Proliferation studies showed that DNA synthesis in cancer cells was modestly decreased (approximately 20%), accompanied by an up to 6.5% in cells in the G0/G1 phase and cyclin D1 expression reduction. The concentrations of estradiol and 5α-dihydrotestosterone were decreased by 26% and 3% respectively. However, supplementation of 5α-dihydrotestosterone produced a significant increase (approximately 35.6%) in the anti-proliferative effect of sulfatase inhibition. This study has clarified sex-hormone control by sulfatase in BC, suggesting that the different roles of estradiol and 5α-dihydrotestosterone can lead to a reduction in the effect of sulfatase inhibition when compared with 17ß-HSD7 inhibition. This suggests that combined treatment of sulfatase inhibitors with 17ß-HSD inhibitors such as the type7 inhibitor could hold promise for hormone-dependent breast cancer.

Pharmacokinetic profile of PBRM in rodents, a first selective covalent inhibitor of 17ß-HSD1 for breast cancer and endometriosis treatments.

The development of a covalent inhibitor of 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is a promising approach for the treatment of hormone-dependent breast cancer and endometriosis. After reporting the steroid derivative PBRM as a first potent covalent inhibitor of 17ß-HSD1 without estrogenic activity, we are now interested in studying its pharmaceutical behavior. The metabolism study in a human liver microsomal preparation showed a gradual transformation of PBRM into PBRM-O, an oxidized ketonic form of PBRM at position C17. Interestingly, PBRM-O also inhibits 17ß-HSD1 and is not estrogenic in estrogen-sensitive T-47D cells. However, when PBRM was injected subcutaneously (sc) in mice, a very small proportion of PBRM-O was measured in a 24 h-time course experiment. A pharmacokinetic study in mice revealed suitable values for half-life (T1/2 = 3.4 h), clearance (CL = 2088 mL/h kg), distribution volume (Vz = 10.3 L/kg) and absolute bioavailability (F = 65%) when PBRM was injected sc at 14.7 mg/kg. A good F value of 33% was also obtained when PBRM was given orally. A tritiated version of PBRM, 3H-PBRM, was synthesized and used for an in vivo biodistribution study that showed its gradual accumulation in various mouse tissues (peak at 6 h) followed by elimination until complete disappearance after 72 h. Elimination was found to occur in feces (93%) and urine (7%) as revealed by a mass balance experiment. PBRM was also evaluated for its toxicity in mice and it was found to be very well tolerated after weekly sc administration (30-405 mg/kg for 8 weeks) or by po administration (300-900 mg/kg for 4 weeks). Overall, these experiments represent important steps in the preclinical characterization of the pharmaceutical behavior of PBRM, as well as for its translation to clinical trials.

Blocking 17ß-hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach.

The enzyme type 1 17ß-hydroxysteroid dehydrogenase (17ß-HSD-1), responsible for generating active 17ß-estradiol (E2) from low-active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition. In this study, we explored the possibility of inhibiting 17ß-HSD-1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17ß-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17ß-HSD-1 activity could be blocked by a specific 17ß-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17ß-HSD-1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17ß-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17ß-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17ß-HSD-1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17ß-HSD-1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17ß-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17ß-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17ß-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Insight into the mode of action and selectivity of PBRM, a covalent steroidal inhibitor of 17ß-hydroxysteroid dehydrogenase type 1.

17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is involved in the biosynthesis of estradiol, the major bioactive endogenous estrogen in mammals, and constitutes an interesting therapeutic target for estrogen-dependent diseases. A steroidal derivative, 3-{[(16ß,17ß)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methyl} benzamide (PBRM), has recently been described as a non-estrogenic, irreversible inhibitor of 17ß-HSD1. However, the mode of action of this inhibitor and its selectivity profile have not yet been elucidated. We assessed PBRM potency via in vitro kinetic measurements. The mechanism of enzyme inactivation was also investigated using interspecies (human, mouse, pig and monkey) comparisons via both in vitro assays and in silico analysis. Mouse and human plasma protein binding of PBRM was determined, whereas its selectivity of action was studied using a wide range of potential off-targets (e.g. GPCR, hERG, CYPs, etc.). The affinity constant (Ki=368nM) and the enzyme inactivation rate (kinact=0.087min-1) values for PBRM were determined with purified 17ß-HSD1. PBRM was found to be covalently linked to the enzyme. A long delay period (i.e. 3-5days) is required to recover 17ß-HSD1 activity following a pretreatment of breast and placenta cell lines with PBRM. Mechanistic analyses showed important interspecies differences of 17ß-HSD1 inhibition which support the importance of inactivation for PBRM effect. Evidences of the potency and selectivity of action presented herein for this first non-estrogenic and steroidal covalent irreversible inhibitor of 17ß-HSD1 warrant its further development as a potential drug candidate for estrogen-dependent disorders.

Phenylbenzenesulfonates and -sulfonamides as 17ß-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis.

17ß-Hydroxysteroid dehydrogenase type 2 (17ß-HSD2) converts the potent estrogen estradiol into the weakly active keto form estrone. Because of its expression in bone, inhibition of 17ß-HSD2 provides an attractive strategy for the treatment of osteoporosis, a condition that is often caused by a decrease of the active sex steroids. Currently, there are no drugs on the market targeting 17ß-HSD2, but in multiple studies, synthesis and biological evaluation of promising 17ß-HSD2 inhibitors have been reported. Our previous work led to the identification of phenylbenzenesulfonamides and -sulfonates as new 17ß-HSD2 inhibitors by ligand-based pharmacophore modeling and virtual screening. In this study, new molecules representing this scaffold were synthesized and tested in vitro for their 17ß-HSD2 activity to derive more profound structure-activity relationship rules.

Comparative investigation of the in vitro inhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17ß-hydroxysteroid dehydrogenase type 1.

The inhibitory effects of 13-epimeric estrones, D-secooxime and D-secoalcohol estrone compounds on human placental 17ß-hydroxysteroid dehydrogenase type 1 isozyme (17ß-HSD1) were investigated. The transformation of estrone to 17ß-estradiol was studied by an in vitro radiosubstrate incubation method. 13α-Estrone inhibited the enzyme activity effectively with an IC50 value of 1.2 µM, which indicates that enzyme affinity is similar to that of the natural estrone substrate. The 13ß derivatives and the compounds bearing a 3-hydroxy group generally exerted stronger inhibition than the 13α and 3-ether counterparts. The 3-hydroxy-13ß-D-secoalcohol and the 3-hydroxy-13α-D-secooxime displayed an outstanding cofactor dependence, i.e. more efficient inhibition in the presence of NADH than NADPH. The 3-hydroxy-13ß-D-secooxime has an IC50 value of 0.070 µM and is one of the most effective 17ß-HSD1 inhibitors reported to date in the literature.

Current knowledge of the multifunctional 17ß-hydroxysteroid dehydrogenase type 1 (HSD17B1).

At the late 1940s, 17ß-HSD1 was discovered as the first member of the 17ß-HSD family with its gene cloned. The three-dimensional structure of human 17ß-HSD1 is the first example of any human steroid converting enzyme. The human enzyme's structure and biological function have thus been studied extensively in the last two decades. In humans, the enzyme is expressed in placenta, ovary, endometrium and breast. The high activity of estrogen activation provides the basis of 17ß-HSD1's implication in estrogen-dependent diseases, such as breast cancer, endometriosis and non-small cell lung carcinomas. Its dual function in estrogen activation and androgen inactivation has been revealed in molecular and breast cancer cell levels, significantly stimulating the proliferation of such cells. The enzyme's overexpression in breast cancer was demonstrated by clinical samples. Inhibition of human 17ß-HSD1 led to xenograft tumor shrinkage. Unfortunately, through decades of studies, there is still no drug using the enzyme's inhibitors available. This is due to the difficulty to get rid of the estrogenic activity of its inhibitors, which are mostly estrogen analogues. New non-steroid inhibitors for the enzyme provide new hope for non-estrogenic inhibitors of the enzyme.

Synthesis and in vitro pharmacological evaluation of N-[(1-benzyl-1,2,3-triazol-4-yl)methyl]-carboxamides on d-secoestrone scaffolds.

An efficient synthesis of several N-[(1-benzyl-1,2,3-triazol-4-yl)methyl]carboxamides in the 13ß- and 13α-d-secoestrone series is reported. Novel triazoles were synthesized via the Cu(I)-catalyzed azide-alkyne cycloaddition of steroidal alkynyl carboxamides and p-substituted benzyl azides. Each of the products was evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF-7, A431 and A2780). Some of them exhibited activities similar to those of the reference agent cisplatin. On change of the substitution pattern of the benzyl group of the azide, great differences in the cell growth-inhibitory properties were observed. The p-alkylbenzyl-substituted triazoles selectively exerted high cytostatic action against A2780 cells, with IC50 values of 1 µM. We investigated the potential inhibitory action exerted on the human 17ß-HSD1 activity of the new secosteroids. Three triazoles effectively suppressed the estrone to 17ß-estradiol conversion with IC50 values in low micromolar range.

Addressing cytotoxicity of 1,4-biphenyl amide derivatives: Discovery of new potent and selective 17ß-hydroxysteroid dehydrogenase type 2 inhibitors.

Four different classes of new 17ß-hydroxysteroid dehydrogenase type 2 (17ß-HSD2) inhibitors were synthesized, in order to lower the cytotoxicity exhibited by the lead compound A, via disrupting the linearity and the aromaticity of the biphenyl moiety. Compounds 3, 4, 7a and 8 displayed comparable or better inhibitory activity and selectivity, as well as a lower cytotoxic effect, compared to the reference compound A. The best compound 4 (IC50=160nM, selectivity factor=168, LD50≈25µM) turned out as new lead compound for inhibition of 17ß-HSD2.

Synthesis of A-ring halogenated 13α-estrone derivatives as potential 17ß-HSD1 inhibitors.

13α-Estrone and its 3-methyl or benzyl ether were halogenated in ring A with N-bromo- or N-iodosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin as electrophile triggers. The chemo- and regioselectivities of the reactions depended greatly on the nature of the substituent on C-3. Bromination of the ethers led to 2- and 4-regioisomers. Bis-halogenation occurred only in the case of the phenolic derivative. Iodination and bromination resulted in similar products, except that the 3-benzyl ether could not be iodinated under the applied conditions. The potential inhibitory action of the new halogenated 13α-estrones on human 17ß-hydroxysteroid dehydrogenase 1 activity was investigated via in vitro radiosubstrate incubation. Some compounds proved to be effective inhibitors, with IC50 values in the submicromolar range.

Type 2 17-ß hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis.

Low estradiol level in postmenopausal women is implicated in osteoporosis, which occurs because of the high bone resorption rate. Estrogen formation is controlled by 17-ß hydroxysteroid dehydrogenase 17-ß HSD enzymes, where 17-ß HSD type 1 contributes in the formation of estradiol, while type 2 catalyzes its catabolism. Inhibiting 17-ß HSD2 can help in increasing estradiol concentration. Several promising 17-ß HSD2 inhibitors that can act at low nanomolar range have been identified. However, there are some specific challenges associated with the application of these compounds. Our review provides an up-to-date summary of the current status and recent progress in the production of 17-ß HSD2 inhibitors as well as the future challenges in their clinical application.

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.