Discovery of diarylhydantoins as new selective androgen receptor modulators
| Autor: | Francois Nique, Denis Guédin, Nicolas Triballeau, Eric Duval, Jean-Michel Lemoullec, Denis Annoot, Catherine Robin-Jagerschmidt, Maxime Thauvin, Jean-Michel Lefrancois, Thierry Prangé, Laurence Michoux, Philippe Clément-Lacroix, Damien Fleury, Pierre Deprez, Patrick Mollat, Séverine Hebbe, Dominique Minet, Christophe Peixoto |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
Models Molecular Transcriptional Activation medicine.medical_specialty Antiandrogens Hydantoin Peptide Pharmacology Crystallography X-Ray Binding Competitive Bone and Bones Transactivation chemistry.chemical_compound Structure-Activity Relationship Anabolic Agents Internal medicine Drug Discovery medicine Androgen Receptor Antagonists Potency Animals Humans Muscle Skeletal chemistry.chemical_classification Hydantoins Prostate Stereoisomerism In vitro Rats Androgen receptor Drug Partial Agonism Endocrinology Selective androgen receptor modulator chemistry Receptors Androgen Androgens Molecular Medicine Orchiectomy HeLa Cells |
| Zdroj: | Journal of medicinal chemistry. 55(19) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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