Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker

Abdelsamie, Ahmed S.; Bey, Emmanuel; Hanke, Nina; Empting, Martin; Hartmann, Rolf W.; Frotscher, Martin

doi:10.1016/j.ejmech.2014.05.074

Cited by 10 publications

(14 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a consequence, one of its proposed therapeutic approaches is the reduction of E2 synthesis by the inhibition of 17β-HSD1 [86]. Several steroidal and non-steroidal 17β-HSD1 inhibitors are under pharmacological investigation targeting endometriosis [87][88][89], and an effort has been made to develop a reliable murine animal model of the disease as well [90].…”

Section: β-Hydroxysteroid-dehydrogenase Inhibitorsmentioning

confidence: 99%

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

Minorics

Zupkó

2018

ACAMC

View full text Add to dashboard Cite

Research of steroidal compounds as anticancer agents started almost 50 years ago. During the past decades, several innovative new steroids, like cyproterone, finasteride, estramustin, exemestane and fulvestrant have successfully become a part of routine clinical practice. Meanwhile, a vast amount of new information have accumulated about the functions of the endogenous steroid system (including the characterization of enzymes, receptors, transcription pathways, etc.) and about the role of steroids in carcinogenesis. Therefore, it is regularly required to review the latest published results, focusing on a well-defined part within this research field that has definitely developed into a highly diversified speciality by now. Herein, we make an attempt to summarize the most recent results reported about anticancer agents of estrane backbone, focusing on their mechanisms of action and their structure-activity relationships. Due to the vast number and various accessibilities of scientific publications, neither other reviews nor this one can be considered as absolutely exhaustive. In spite of these restrictive factors, the current review makes a good opportunity to define the recent scientific trends in the field of estradiol-related anticancer agents.

show abstract

Section: β-Hydroxysteroid-dehydrogenase Inhibitorsmentioning

confidence: 99%

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

Minorics

Zupkó

2018

ACAMC

View full text Add to dashboard Cite

show abstract

“…Computational methods were used to elucidate its interactions with the target protein. The compound also showed activity towards the murine 17β-HSD1 enzyme and is thus a starting point for the design of compounds suitable for evaluation in an animal disease model (Abdelsamie et al, 2014).…”

Section: Inhibitor Designmentioning

confidence: 99%

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

He¹,

Misra

et al. 2016

Gene

View full text Add to dashboard Cite

At the late 1940s, 17β-HSD1 was discovered as the first member of the 17β-HSD family with its gene cloned. The three-dimensional structure of human 17β-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 17β-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 17β-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.

show abstract

“…Human, mouse, and rat 17β-HSD2 preparations were obtained by isolating the microsomal fractions of human placenta, mouse, and rat liver homogenates, respectively, according to described methods. ,,, Incubations were run with [ 3 H]-E2 (human: 500 nM; mouse and rat: 10 nM), cofactor NAD + , and inhibitor. Human 17β-HSD1 was prepared from the cytosolic fractions of human placenta, whereas recombinant mouse and rat 17β-HSD1 cDNAs (OriGene, USA) were transiently expressed in HEK293 cells and prepared by ammonium sulfate precipitation essentially as described for human 17β-HSD1 preparation.…”

Section: Methodsmentioning

confidence: 99%

“…Separation and measurement of the substrate and product were accomplished by radio HPLC. Metabolic stabilities in human, mouse, and rat liver S9 fractions were determined in the presence of the cofactors NADP, uridine diphosphate glucuronic acid (UDPGA), and PAPS, as described earlier. ,,− The cellular h 17β-HSD2 inhibitory activity of compounds was measured using the breast cancer cell-line MDA-MB-231 (having negligible 17β-HSD1 activity) with 200 nM [ 3 H]-E2 as the substrate and incubated for 6 h at 37 °C . After ether extraction, the substrate and product were separated and measured as described above.…”

Section: Methodsmentioning

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

Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker

Cited by 10 publications

References 52 publications

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

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

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

Contact Info

Product

Resources

About