Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker
| Autor: | Martin Empting, Martin Frotscher, Rolf W. Hartmann, Ahmed S. Abdelsamie, Emmanuel Bey, Nina Hanke |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular 17-Hydroxysteroid Dehydrogenases medicine.drug_class Stereochemistry Dehydrogenase Sulfides chemistry.chemical_compound Mice Structure-Activity Relationship Thioether Biosynthesis Phenols Drug Discovery medicine Animals Humans Enzyme Inhibitors Pharmacology chemistry.chemical_classification Bicyclic molecule Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry General Medicine Enzyme Biochemistry Estrogen Target protein Linker hormones hormone substitutes and hormone antagonists |
| Popis: | Estradiol is the most potent estrogen in humans. It is known to be involved in the development and proliferation of estrogen dependent diseases such as breast cancer and endometriosis. The last step of its biosynthesis is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β- HSD1) which consequently is a promising target for the treatment of these diseases. Recently, we reported on bicyclic substituted hydroxyphenylmethanones as potent inhibitors of 17β-HSD1. The present study focuses on rational structural modifications in this compound class with the aim of gaining more insight into its structure-activity relationship (SAR). (4-Hydroxyphenyl)-(5-(3-hydroxyphenylsulfanyl)-thiophen-2-yl)methanone (25) was discovered as a member of a novel potent class of human 17β-HSD1 inhibitors. Computational methods were used to elucidate its interactions with the target protein. The compound showed activity also towards the murine 17β-HSD1 enzyme and thus is a starting point for the design of compounds suitable for evaluation in an animal disease model. |
| Databáze: | OpenAIRE |
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