Discovery of Diarylhydantoins as New Selective Androgen Receptor Modulators

被引：68

作者：

Nique, Francois ^{[1
]}

Hebbe, Severine ^{[1
]}

Peixoto, Christophe ^{[1
]}

Annoot, Denis ^{[1
]}

Lefrancois, Jean-Michel ^{[1
]}

Duval, Eric ^{[1
]}

Michoux, Laurence ^{[1
]}

Triballeau, Nicolas ^{[1
]}

Lemoullec, Jean-Michel ^{[1
]}

Mollat, Patrick ^{[1
]}

Thauvin, Maxime ^{[2
]}

Prange, Thierry ^{[2
]}

Minet, Dominique ^{[1
]}

Clement-Lacroix, Philippe ^{[1
]}

Robin-Jagerschmidt, Catherine ^{[1
]}

Fleury, Damien ^{[1
]}

Guedin, Denis ^{[1
]}

Deprez, Pierre ^{[1
]}

机构：

[1] GALAPAGOS, F-93230 Romainville, France

[2] Univ Paris 05, UMR CNRS 8015, F-75006 Paris, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 19期

关键词：

LIGAND-BINDING DOMAINS; MULTIFUNCTIONAL MEDICINES; OLDER MEN; TESTOSTERONE; EFFICACY; ANTIESTROGENS; ANTIANDROGEN; CANDIDATE; THERAPY; AGONIST;

D O I：

10.1021/jm300249m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel selective androgen receptor modulator scaffold has been discovered through structural modifications of hydantoin antiandrogens. Several 4-(4-hydroxyphenyl)-N-arylhydantoins displayed partial agonism with nanomolar in vitro potency in transactivation experiments using androgen receptor (AR) transfected cells. In a standard castrated male rat model, several compounds showed good anabolic activity on levator ani muscle, dissociated from the androgenic activity on ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile ((+)-11b) displayed anabolic potency with a strong dissociation between levator ani muscle and ventral prostate (A(50) = 0.5 mg/kg vs 70 mg/kg). The binding modes of two compounds, including (+)-11b, within the AR ligand-binding domain have been studied by cocrystallization experiments using a coactivator-like peptide. Both compounds bound to the same site, and the overall structures of the AR were very similar.

引用

页码：8225 / 8235

页数：11

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