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.
Mol Cell Endocrinol
; 301(1-2): 205-11, 2009 Mar 25.
Article
en En
| MEDLINE
| ID: mdl-18950679
ABSTRACT
17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the transformation of estrone (E1) into the most potent estrogen, estradiol (E2), which stimulates cell proliferation and decreases apoptosis. 17beta-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 17beta-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)=20nM). Compound 18 also showed a good selectivity toward 17beta-HSD2 and the estrogen receptors alpha and beta.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Modelos Moleculares
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Inhibidores Enzimáticos
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Estradiol Deshidrogenasas
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Naftalenos
Límite:
Humans
Idioma:
En
Revista:
Mol Cell Endocrinol
Año:
2009
Tipo del documento:
Article
País de afiliación:
Alemania