Discovery of diarylhydantoins as new selective androgen receptor modulators.
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.
GALAPAGOS, Parc Biocitech, 102 Avenue Gaston Roussel, 93230 Romainville, France.
François
F
Nique
Séverine
S
Hebbe
Christophe
C
Peixoto
Denis
D
Annoot
Jean-Michel
JM
Lefrançois
Eric
E
Duval
Laurence
L
Michoux
Nicolas
N
Triballeau
Jean-Michel
JM
Lemoullec
Patrick
P
Mollat
Maxime
M
Thauvin
Thierry
T
Prangé
Dominique
D
Minet
Philippe
P
Clément-Lacroix
Catherine
C
Robin-Jagerschmidt
Damien
D
Fleury
Denis
D
Guédin
Pierre
P
Deprez
D045930:Anabolic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000728:Androgens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001842:Bone and Bones / Q000187:drug effects / Q000502:physiology; D018360:Crystallography, X-Ray; D054333:Drug Partial Agonism; D006367:HeLa Cells; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009919:Orchiectomy; D011467:Prostate / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
C577109:4-(3,4-dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; D045930:Anabolic Agents; D059002:Androgen Receptor Antagonists; D000728:Androgens; D006827:Hydantoins; D011944:Receptors, Androgen