Structure-activity study in the class of 6-(3'-hydroxyphenyl)naphthalenes leading to an optimization of a pharmacophore model for 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitors
| Autor: | Ruth Werth, Sandrine Marchais-Oberwinkler, Erika Ziegler, Hubert Thole, Patricia Kruchten, Rolf W. Hartmann, Josef Messinger, Martin Frotscher |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular medicine.drug_class Estrogen receptor Dehydrogenase Estrone Naphthalenes Biochemistry Estradiol Dehydrogenases 03 medical and health sciences chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship 0302 clinical medicine Endocrinology medicine Humans Hydroxysteroid dehydrogenase Enzyme Inhibitors Molecular Biology ComputingMilieux_MISCELLANEOUS 030304 developmental biology chemistry.chemical_classification 0303 health sciences Chemistry Cell growth Life Sciences 3. Good health Enzyme Estrogen 030220 oncology & carcinogenesis Pharmacophore hormones hormone substitutes and hormone antagonists |
| Zdroj: | Molecular and Cellular Endocrinology Molecular and Cellular Endocrinology, Elsevier, 2009, 301 (1-2), pp.205. ⟨10.1016/j.mce.2008.09.024⟩ |
| ISSN: | 0303-7207 |
| DOI: | 10.1016/j.mce.2008.09.024⟩ |
| Popis: | 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the transformation of estrone (E1) into the most potent estrogen, estradiol (E2), which stimulates cell proliferation and decreases apoptosis. 17β-HSD1 is often strongly overexpressed in estrogen-dependent diseases (like breast cancer and endometriosis). Thus, this over expressed enzyme is a promising novel target for the development of selective inhibitors, which could be used as drugs for the treatment of these diseases. Using a structure- and ligand-based approach, a pharmacophore model was proposed and a new class of non-steroidal inhibitors of 17β-HSD1 was designed. Enzyme inhibition was evaluated in vitro using the human enzyme. After identification of the 6-(3′-hydroxyphenyl)-2-naphthol scaffold 1 , the potency of this class of inhibitors was further improved by substitution of the 1-position of the naphthalene ring by a phenyl group (compound 18 , IC 50 = 20 nM). Compound 18 also showed a good selectivity toward 17β-HSD2 and the estrogen receptors α and β. |
| Databáze: | OpenAIRE |
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