Non-steroidal L-245,976 acts as a classical antiandrogen in vitro.
Non-steroidal antiandrogens have been employed in the management of prostate cancer, but the mechanism of action is unclear due to a lack of good tissue culture models. The growth of a hamster ductus deferens cell line (DDT1) is highly dependent upon the addition of 10 nM testosterone to synthetic serum-free media. We describe a non-steroidal compound N-(4-chlorophenyl)-(Z,Z)-2,3-bis(-cyclopropylmethylene) cyclopentanecarboxamide (L-245976) which antagonizes the action of testosterone on DDT1 cells at 10 microM but exhibits little or no effect on cell growth by itself. This compound also blocks the binding of 3H-dihydrotestosterone (DHT) to the human androgen receptor (AR) with an IC50 of approximately 28 microM. In addition, L-245976 was found to antagonize DHT-dependent transactivation of the AR via the probasin gene promoter at comparable doses with no agonist activity.
Toney
J H
JH
Department of Biochemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, U.S.A.
Chen
Y
Y
Rutledge
S J
SJ
Schmidt
A
A
Elbrecht
A
A
D000577:Amides / Q000494:pharmacology*; D000726:Androgen Antagonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000727:Androgen-Binding Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003124:Colorimetry / Q000379:methods; D006224:Cricetinae; D013196:Dihydrotestosterone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005485:Flutamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D005562:Formazans / Q000378:metabolism; D006801:Humans; D008297:Male; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000032:analysis / Q000378:metabolism; D013844:Thiazoles / Q000032:analysis / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014649:Vas Deferens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D000577:Amides; D000726:Androgen Antagonists; D000727:Androgen-Binding Protein; D000728:Androgens; D000814:Aniline Compounds; D005562:Formazans; C106499:L 245976; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; C027519:probasin; D013196:Dihydrotestosterone; C070380:3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; C014290:hydroxyflutamide; D013739:Testosterone; D005485:Flutamide