Discovery of Diarylhydantoins as New Selective Androgen Receptor Modulators

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• 作者：Fran莽ois Nique ; S茅verine Hebbe ; Christophe Peixoto ; Denis Annoot ; Jean-Michel Lefran莽ois ; Eric Duval ; Laurence Michoux ; Nicolas Triballeau ; Jean-Michel Lemoullec ; Patrick Mollat ; Maxime Thauvin ; Thierry Prang茅 ; Dominique Minet ; Philippe Cl茅ment-Lacroix ; Catherine Robin-Jagerschmidt ; Damien Fleury ; Denis Gu茅din ; Pierre Deprez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8225-8235
• 全文大小：424K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

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 (A₅₀ = 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.