3V4A

Structure of ar lbd with activator peptide and sarm inhibitor 2

Summary for 3V4A

• Entry DOI: 10.2210/pdb3v4a/pdb
• Related: 2AMA 2Z4J 3V49
• Descriptor: Androgen receptor, (5R)-3-(3,4-dichlorophenyl)-5-(4-hydroxyphenyl)-1,5-dimethyl-2-thioxoimidazolidin-4-one, SULFATE ION, ... (5 entities in total)
• Functional Keywords: diarylhydantoin, synthesis, antiandrogen, androgen receptor, testosterone, selective androgen receptor modulator, dihydrotestosterone, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : P10275 P10275
• Total number of polymer chains: 2
• Total formula weight: 30790.83

Authors

Nique, F.,Hebbe, S.,Peixoto, C.,Annoot, D.,Lefrancois, J.-M.,Duval, E.,Michoux, L.,Triballeau, N.,Lemoullec, J.M.,Mollat, P.,Thauvin, M.,Prange, T.,Minet, D.,Clement-Lacroix, P.,Robin-Jagerschmidt, C.,Fleury, D.,Guedin, D.,Deprez, P. (deposition date: 2011-12-14, release date: 2012-09-05, Last modification date: 2023-09-13)

Primary citation

Nique, F.,Hebbe, S.,Peixoto, C.,Annoot, D.,Lefrancois, J.-M.,Duval, E.,Michoux, L.,Triballeau, N.,Lemoullec, J.M.,Mollat, P.,Thauvin, M.,Prange, T.,Minet, D.,Clement-Lacroix, P.,Robin-Jagerschmidt, C.,Fleury, D.,Guedin, D.,Deprez, P.
Discovery of diarylhydantoins as new selective androgen receptor modulators.
J.Med.Chem., 55:8225-8235, 2012

PubMed Abstract: 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.

PubMed: 22897611
DOI: 10.1021/jm300249m

Experimental method

X-RAY DIFFRACTION (1.95 Å)