Treatment of estrogen-dependent diseases: Design, synthesis and profiling of a selective 17β-HSD1 inhibitor with sub-nanomolar IC 50 for a proof-of-principle study

Abdelsamie, Ahmed S.; Koppen, Chris J. van; Bey, Emmanuel; Salah, Mohamed; Börger, Carsten; Siebenbürger, Lorenz; Laschke, Matthias W.; Menger, Michael D.; Frotscher, Martin

doi:10.1016/j.ejmech.2016.11.004

Cited by 15 publications

(29 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HSD inhibitors are being studied in the area of hormone-dependent diseases, with 11βHSD inhibitors being in clinical trials for metabolic disorders (Ye et al, 2017 ) and 17βHSD inhibitors approaching the clinical phase for a number of gynecological indications (Table 3 ; Abdelsamie et al, 2017 ).…”

Section: Drug Developmentmentioning

confidence: 99%

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

et al. 2018

View full text Add to dashboard Cite

Our understanding of the intracrine (or local) regulation of estrogen and other steroid synthesis and degradation expanded in the last decades, also thanks to recent technological advances in chromatography mass-spectrometry. Estrogen responsive tissues and organs are not passive receivers of the pool of steroids present in the blood but they can actively modify the intra-tissue steroid concentrations. This allows fine-tuning the exposure of responsive tissues and organs to estrogens and other steroids in order to best respond to the physiological needs of each specific organ. Deviations in such intracrine control can lead to unbalanced steroid hormone exposure and disturbances. Through a systematic bibliographic search on the expression of the intracrine enzymes in various tissues, this review gives an up-to-date view of the intracrine estrogen metabolisms, and to a lesser extent that of progestogens and androgens, in the lower female genital tract, including the physiological control of endometrial functions, receptivity, menopausal status and related pathological conditions. An overview of the intracrine regulation in extra gynecological tissues such as the lungs, gastrointestinal tract, brain, colon and bone is given. Current therapeutic approaches aimed at interfering with these metabolisms and future perspectives are discussed.

show abstract

Section: Drug Developmentmentioning

confidence: 99%

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Compound B belongs to the class of bicyclic-substituted hydroxyphenylmethanones which were thoroughly studied as 17β-HSD2 and 1 inhibitors in our recent reports. ,− Based on the structure–activity relationship (SAR) derived for this class, the ABC system is considered the core structure, and the phenolic hydroxyl group is crucial for the 17β-HSD2 activity. The fluorosubstitution pattern around the phenolic hydroxyl group is essential for providing metabolic stability of the compounds.…”

Section: Resultsmentioning

confidence: 99%

“…C NMR (125 MHz, acetone-d 6 ): δ 183.0, 167.1, 165.1, 157.9 (dd, J = 253.1, 11.1 Hz), 157.2 (dd, J = 254.2, 12.6 Hz), 148.1 (ddd, J = 244.1, 11.0, 3.0 Hz), 147.1 (ddd, J = 244.3, 4.2, 2.9 Hz), 145.7−143.7 (m), 143.7 (ddd, J = 248.7, 15.8, 5.8 Hz), 137.4 (d, J = 1.9 Hz), 137.2−137.0 (m), 136.9 (d, J = 3.1 Hz), 131.0 (d, J = 9.6 Hz), 128.8 (d, J = 4.9 Hz), 127.7 (dd, J = 4.2, 2.0 Hz), 123.1−122.8 (m), 122.8 (dd, J = 13.7, 3.6 Hz), 118.6 (dd, J = 13.8, 4.2 Hz), 117.2 (d, J = 23.0 Hz), 107.0 (dd, J = 21.1, 3.0 Hz), 106.4 (dd, J = 27.8, 24.7 Hz); HRMS m/z: 544.00702 (M + H) + C 23 H 12 F 6 NO 4 S 2 + calcd, 544.01064; UV λ (nm) = 235, 352; RT HPLC = 7.98 min (13 min 10−95% MeCN in water with 0.1% formic acid).4-Fluoro-N-(4-(5-(2,4,5-trifluoro-3-hydroxybenzoyl)thiophen-2yl)phenyl)benzene-sulfonamide(23). The title compound was prepared by reaction of (5-(4-aminophenyl)thiophen-2-yl)(2,4,5trifluoro-3-methoxyphenyl)methanone (8) (145 mg, 0.4 mmol), and 4-fluorobenzenesulfonyl chloride (97 mg, 0.5 mmol), according to method C. The crude product was reacted with boron tribromide (3 equiv), according to method D. The product was purified by preparative HPLC; yield over two steps: 8% (16 mg);1 H NMR (500 MHz, acetone-d 6 ): δ 10.02 (br s, 1H), 9.36 (br s, 1H), 7.99−7.88 (m, 2H), 7.74−7.67 (m, 2H), 7.63 (dd, J = 4.0, 1.7 Hz, 1H), 7.49 (d, J = 4.1 Hz, 1H), 7.37−7.28 (m, 4H), 7.08 (ddd, J = 9.8, 8.2, 5.6 Hz, 1H).…”

mentioning

confidence: 99%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

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 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2), may be more efficacious in the treatment of osteoporosis. Blockade of 17β-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 17β-HSD2 inhibitor (compound 24). Compound 24 is a nanomolar potent inhibitor of human 17β-HSD2 (IC50 of 6.1 nM) and rodent 17β-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.

show abstract

“…E2B in Figure 1(C) ) and non-steroidal (see e.g. 11–13 ) compounds are known to inhibit the HSD1 activity, but none of these promising leads has passed clinical trials so far. There are also several X-ray crystal structures of HSD1 in both ligand-free, substrate-, and inhibitor-bound states to facilitate rational structure-based drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives

Niinivehmas

Postila

Rauhamäki

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking oestradiol synthesis by 17-β-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase pathway. Five analogues produced ≥62% HSD1 inhibition at 5 µM and, furthermore, three of them produced ≥68% inhibition at 1 µM. A docking-based structure-activity relationship analysis was done to determine the molecular basis of the inhibition and the cross-reactivity of the analogues was tested against oestrogen receptor, aromatase, cytochrome P450 1A2, and monoamine oxidases. Most of the analogues are only modestly active with 17-β-hydroxysteroid dehydrogenase 2 – a requirement for lowering effective oestradiol levels in vivo. Moreover, the analysis led to the synthesis and discovery of 3-imidazolecoumarin as a potent aromatase inhibitor. In short, coumarin core can be tailored with specific ring and polar moiety substitutions to block either the sulphatase pathway or the aromatase pathway for treating breast cancer and endometriosis.

show abstract

Treatment of estrogen-dependent diseases: Design, synthesis and profiling of a selective 17β-HSD1 inhibitor with sub-nanomolar IC 50 for a proof-of-principle study

Cited by 15 publications

References 34 publications

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

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

Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives

Contact Info

Product

Resources

About