84954-08-5Relevant articles and documents
Discovery of diarylhydantoins as new selective androgen receptor modulators
Nique, Francois,Hebbe, Severine,Peixoto, Christophe,Annoot, Denis,Lefrancois, Jean-Michel,Duval, Eric,Michoux, Laurence,Triballeau, Nicolas,Lemoullec, Jean-Michel,Mollat, Patrick,Minet, Dominique,Clement-Lacroix, Philippe,Robin-Jagerschmidt, Catherine,Fleury, Damien,Guedin, Denis,Deprez, Pierre,Thauvin, Maxime,Prange, Thierry
supporting information, p. 8225 - 8235,11 (2020/09/15)
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.
Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators
Hamann, Lawrence G.,Manfredi, Mark C.,Sun, Chongqing,Krystek Jr., Stanley R.,Huang, Yanting,Bi, Yingzhi,Augeri, David J.,Wang, Tammy,Zou, Yan,Betebenner, David. A.,Fura, Aberra,Seethala, Ramakrishna,Golla, Rajasree,Kuhns, Joyce E.,Lupisella, John A.,Darienzo, Celia J.,Custer, Laura L.,Price, Jennifer L.,Johnson, James M.,Biller, Scott A.,Zahler, Robert,Ostrowski, Jacek
, p. 1860 - 1864 (2008/02/04)
Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.
