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

Perspicace, Enrico; Cozzoli, Liliana; Gargano, Emanuele M.; Hanke, Nina; Carotti, Angelo; Hartmann, Rolf W.; Marchais‐Oberwinkler, Sandrine

doi:10.1016/j.ejmech.2014.06.036

Cited by 16 publications

(11 citation statements)

References 44 publications

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“…Other pathways proteins. 17β-HSD2 is a microsomal enzyme that catalyzes the oxidation of sex steroids testosterone and estradiol (E2) to less active ketones androstenedione and estrone (E1) 85,86 . It is reported that the inhibition of 17β-HSD2 in a in vivo monkey model and osteoporosis patients is beneficial to increase in E2 and testosterone levels that facilitate reduction in bone resorption and maintenance of bone formation 87 .…”

Section: Discussionmentioning

confidence: 99%

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Tiwari

Mishra

Salemi

et al. 2020

Sci Rep

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Ibuprofen, an inhibitor of prostanoid biosynthesis, is a common pharmacological agent used for the management of pain, inflammation and fever. However, the chronic use of ibuprofen at high doses is associated with increased risk for cardiovascular, renal, gastrointestinal and liver injuries. The underlying mechanisms of ibuprofen-mediated effects on liver remain unclear. To determine the mechanisms and signaling pathways affected by ibuprofen (100 mg/kg/day for seven days), we performed proteomic profiling of male mice liver with quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) using ten-plex tandem mass tag (TMT) labeling. More than 300 proteins were significantly altered between the control and ibuprofen-treated groups. The data suggests that several major pathways including (1) energy metabolism, (2) protein degradation, (3) fatty acid metabolism and (4) antioxidant system are altered in livers from ibuprofen treated mice. Independent validation of protein changes in energy metabolism and the antioxidant system was carried out by Western blotting and showed sex-related differences. Proteasome and immunoproteasome activity/expression assays showed ibuprofen induced gender-specific proteasome and immunoproteasome dysfunction in liver. The study observed multifactorial gender-specific ibuprofen-mediated effects on mice liver and suggests that males and females are affected differently by ibuprofen. Ibuprofen, a propionic acid derivative, is the most common over-the-counter nonsteroidal anti-inflammatory (NSAID) drug used to treat fever, pain, inflammation and many other disorders 1. It has been included as a major medicine in the Essential Drugs List of the World Health Organization 2. Ibuprofen at low over-the-counter doses (800-1200 mg/day) is used to treat muscular aches, backaches, toothaches, and fever. At higher doses (1800-2400 mg/day), ibuprofen is prescribed for the treatment of chronic conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis 3. Ibuprofen is a non-selective inhibitor of the cyclo-oxygenase (COX) isozymes COX-1 and COX-2 that converts arachidonic acid into prostaglandins including thromboxane and prostacyclin 1. The anti-inflammatory, antipyretic and analgesic effects of ibuprofen are mediated through the inhibition of prostaglandins E2 (PGE2) and I2 (PGI2) production by blocking COX activity 1. Both PGE2 and PGI2 are pro-inflammatory prostanoids that increase vascular permeability, promote leukocyte infiltration and increase edema formation 4. The clearance of ibuprofen is mediated through oxidative metabolism by multiple cytochrome P450 (CYP) enzymes (CYP2C9, CYP2C8) to inactive primary metabolites including 3-hydroxy-ibuprofen, carboxy ibuprofen and 2-hydroxy-ibuprofen 5,6. Most of the ibuprofen is metabolized in liver, while only a small percentage of unchanged drug is excreted in the urine 5. The liver plays a key role in energy metabolism and is essential for whole body homeostasis via the regulation of glucose, lipid, and amino acid ...

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Section: Discussionmentioning

confidence: 99%

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Tiwari

Mishra

Salemi

et al. 2020

Sci Rep

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“…All other newly discovered 17β-HSD2 inhibitors were preferentially selective over 17β-HSD1, and therefore they could serve as lead structures for further optimization. It needs to be noted that the activities of these compounds toward 17β-HSD2 are at least an order of magnitude lower than that of reported synthetic, chemically optimized compounds. ,, To further develop potential lead candidates, additional investigations into the bioavailability, metabolism, and tissue distribution of the identified natural compounds are needed. Inhibition of 17β-HSD2 is expected to result in tissue-specific elevated levels of estradiol, and potential adverse effects include endometrial hyperplasia and impaired growth control of the glandular epithelium of the breast. − Thus, compounds that are primarily active in the bone would be preferred for future drug development.…”

Section: Resultsmentioning

confidence: 99%

“…Both compounds are potential natural lead structures that could be used for the development of 17β-HSD2 drug candidates. Unlike many other related compounds that are possibly rapidly metabolized due to the presence of several hydroxy groups, 2-(3-chloro-4hydroxyphenyl)-N-(2-chlorobenzyl)acetamide (18) has only a single hydroxy group and might therefore be less prone to rapid biotransformation. Compound 18 still potently and selectively inhibited 17β-HSD2 with an IC 50 of 0.78 ± 0.16 μM.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Although multiple synthetic 17β-HSD2 inhibitors have already been reported, − natural products inhibiting this enzyme are currently underexplored. There are only a few reports on natural product inhibitors of 17β-HSD2 and other steroid-metabolizing enzymes, and the majority of these compounds are flavonoids. − Flavonoids share certain functional similarities with steroids and can be considered as steroid mimetics (Figure S1, Supporting Information).…”

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Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

et al. 2017

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17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ4-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17β-HSD2 with nanomolar to low micromolar IC50 values. The most potent compounds, nordihydroguaiaretic acid (1), IC50 0.38 ± 0.04 μM, (−)-dihydroguaiaretic acid (4), IC50 0.94 ± 0.02 μM, isoliquiritigenin (6), IC50 0.36 ± 0.08 μM, and ethyl vanillate (12), IC50 1.28 ± 0.26 μM, showed 8-fold or higher selectivity over 17β-HSD1. As some of the identified compounds belong to the same structural class, structure–activity relationships were derived for these molecules. Thus, this study describes new 17β-HSD2 inhibitors from nature and provides insights into the binding pocket of 17β-HSD2, offering a promising starting point for further research in this area.

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“…In addition, a number of thiophene‐2‐carboxamide derivatives have been detailed as potent inhibitors of VEGF . We envisioned that one of the essential pharmacophore of ZD6474 and their analogues include the quinazoline ring and it was thought that it would be worthwhile to synthesize some new quinazoline derivatives bearing a thiophene‐2‐carboxamide derivative at the C‐4 position of 6,7‐dimethoxyquinazoline.…”

Section: Introductionmentioning

confidence: 99%

6,7‐Dimethoxy‐quinazolin‐4‐yl‐amino‐thiophene‐2‐carboxamides as Potent Inhibitors of VEGF Receptors 1 and 2

Ashok

Thanukrishnan

Naik

et al. 2016

Journal of Heterocyclic Chem

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The identification of agents with antiproliferative activity against endothelial cells has significant value for the treatment of many angiogenesis‐dependent pathologies. The vascular endothelial growth factor (VEGF) and its receptors have been implicated as key factors in tumor angiogenesis and are major targets in cancer therapy. A series of novel 6,7‐dimethoxy‐quinazolin‐4‐yl‐amino‐thiophene‐2‐carboxamides were synthesized and evaluated as antagonists of VEGFR‐1 and VEGFR‐2. More specifically, several analogues exhibited low micromolar to nanomolar potency in the inhibition of VEGFR‐1 and VEGFR‐2. The most potent compound in this series, compound 7b, was found to be a potent inhibitor of VEGFR‐2 in a homogeneous time‐resolved fluorescence enzymatic assay with an IC50 as low as 87 nm.

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

Cited by 16 publications

References 44 publications

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

6,7‐Dimethoxy‐quinazolin‐4‐yl‐amino‐thiophene‐2‐carboxamides as Potent Inhibitors of VEGF Receptors 1 and 2

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