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

European Journal of Medicinal Chemistry
Ahmed S AbdelsamieMartin Frotscher

Abstract

17β-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. 17β-Hydroxysteroid dehydrogenase type 1 (17β-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 17β-HSD1, but marginal activity towards rodent 17β-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) 17β-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 17β-HSD1 up to date (IC₅₀ = 2 nM and 97 nM, respectively).

References

Feb 1, 1984·Cancer·D B Thomas
Mar 4, 2000·Endocrine Reviews·J G Liehr
May 4, 2004·Chembiochem : a European Journal of Chemical Biology·Hans-Joachim BöhmMartin Stahl
Nov 11, 2005·Journal of Medicinal Chemistry·Andrea CavalliMaurizio Recanatini
Jul 29, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jose RussoIrma H Russo
Dec 22, 2006·Journal of Medicinal Chemistry·Andrew V Razgulin, Sandro Mecozzi
Apr 25, 2007·Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology·Tina SmucTea Lanisnik Rizner
Sep 29, 2007·Science·Klaus MüllerFrançois Diederich
Jan 27, 2009·The Journal of Steroid Biochemistry and Molecular Biology·Agneta Jansson
Jan 5, 2011·The Journal of Steroid Biochemistry and Molecular Biology·Sandrine Marchais-OberwinklerJerzy Adamski
Sep 13, 2012·The Journal of Clinical Endocrinology and Metabolism·Kaisa HuhtinenMatti Poutanen

❮ Previous
Next ❯

Citations

Jul 6, 2018·Expert Opinion on Pharmacotherapy·Simone FerreroFabio Barra
Mar 14, 2017·The Journal of Steroid Biochemistry and Molecular Biology·Katharina R BeckAlex Odermatt

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.