Discovery of Diarylhydantoins as New Selective Androgen Receptor Modulators

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.

Characterization of GLPG0492, a selective androgen receptor modulator, in a mouse model of hindlimb immobilization

“…GLPG0492 has been previously tested in a standard castrated male rodent model in which it demonstrated after oral dosing robust anabolic activity on levator ani (LA) muscle comparable to testosterone propionate, but dissociated from the androgenic activity on ventral prostate. The dose displaying 50% activity on LA was 0.75 mg/kg/day, while at the maximum 30% activity can be achieved on prostate at the highest dose tested[27]. So, GLPG0492 has demonstrated a robust selectivity for muscle versus prostate, as SARM[26, 27].…”

“…The dose displaying 50% activity on LA was 0.75 mg/kg/day, while at the maximum 30% activity can be achieved on prostate at the highest dose tested[27]. So, GLPG0492 has demonstrated a robust selectivity for muscle versus prostate, as SARM[26, 27]. …”

Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists

“…In addition, three aminoacid residues positioned close to His874 were also suggested to be not strictly rigid in their native location. In silico modeling procedure was then performed for compounds (R)-6e9 in ICM-Pro software [32] using the crystallographic structures published previously by Nique and colleagues [33] (PDB codes: 3V49 and 3V4A) as the major 3D template. Binding site was then completely reconstructed with flexible points assigned to His874, W741, M742 and I899.…”

Ligand fishing using new chitosan based functionalized Androgen Receptor magnetic particles

“…For example, high-throughput screening techniques, where a rapid assay is carried out to determine the biological or biochemical activity of a large number of drug-like compounds, has been used to study the interactions of endocrine disrupting chemicals with the AR [4]. As a result, HTS is useful for the discovery and identification of new selective androgen receptor modulators [6,7]. Another method developed for the identification of novel AR ligands is the AR binding-screening assays.…”