Design, synthesis, and biological evaluation of (hydroxyphenyl)naphthalene and -quinoline derivatives: potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) for the treatment of estrogen-dependent diseases.

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Frotscher M, Ziegler E, Marchais-Oberwinkler S, Kruchten P, Neugebauer A, Fetzer L, Scherer C, Muller-Vieira U, Messinger J, Thole H, Hartmann RW

J Med Chem. 2008 Apr 10;51(7):2158-69. doi: 10.1021/jm701447v. Epub 2008 Mar 7.

PubMed ID

18324762 [ View in PubMed

]

Abstract

Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent estradiol (E2). This reaction takes place in the target cell where the estrogenic effect is exerted via the estrogen receptor (ER). Estrogens, especially E2, are known to stimulate the proliferation of hormone-dependent diseases. 17beta-HSD1 is overexpressed in many breast tumors. Thus, it is an attractive target for the treatment of these diseases. Ligand- and structure-based drug design led to the discovery of novel, selective, and potent inhibitors of 17beta-HSD1. Phenyl-substituted bicyclic moieties were synthesized as mimics of the steroidal substrate. Computational methods were used to obtain insight into their interactions with the protein. Compound 5 turned out to be a highly potent inhibitor of 17beta-HSD1 showing good selectivity (17beta-HSD2, ERalpha and beta), medium cell permeation, reasonable metabolic stability (rat hepatic microsomes), and little inhibition of hepatic CYP enzymes.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
EM-1745	Estradiol 17-beta-dehydrogenase 1	IC 50 (nM)	52	N/A	N/A	Details
Quinidine	Cytochrome P450 2D6	IC 50 (nM)	11	N/A	N/A	Details
Sulfaphenazole	Cytochrome P450 2C9	IC 50 (nM)	250	N/A	N/A	Details