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

Abstract：

: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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Abdelsamie AS,Bey E,Hanke N,Empting M,Hartmann RW,Frotscher M

doi

10.1016/j.ejmech.2014.05.074

subject

Has Abstract

pub_date

2014-07-23 00:00:00

pages

394-406

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(14)00506-6

journal_volume

82

pub_type

杂志文章

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