Non-steroidal L-245,976 acts as a classical antiandrogen in vitro

• Published in: The Journal of steroid biochemistry and molecular biology 1997, Vol.60 (1), p.131-136
• Main Authors: Toney, Jeffrey H., Chen, Yuli, Rutledge, Sue-Jane, Schmidt, Azriel, Elbrecht, Alex
• Format: Article
• Language: English
• Subjects: Amides - pharmacology; Androgen Antagonists - chemistry; Androgen Antagonists - metabolism; Androgen Antagonists - pharmacology; Androgen-Binding Protein - drug effects; Androgen-Binding Protein - genetics; Androgen-Binding Protein - metabolism; Androgens - metabolism; Androgens - pharmacology; Aniline Compounds - pharmacology; Animals; Antineoplastic agents; Biological and medical sciences; Cell Division - drug effects; Cell Line; Chemotherapy; CHO Cells - metabolism; Colorimetry - methods; Cricetinae; Dihydrotestosterone - metabolism; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Flutamide - analogs & derivatives; Flutamide - metabolism; Flutamide - pharmacology; Formazans - metabolism; Humans; Male; Medical sciences; Pharmacology. Drug treatments; Receptors, Androgen - drug effects; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Testosterone - pharmacology; Tetrazolium Salts - analysis; Tetrazolium Salts - metabolism; Thiazoles - analysis; Thiazoles - metabolism; Transcriptional Activation; Transfection; Vas Deferens - cytology; Vas Deferens - drug effects; Vas Deferens - metabolism
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/S0960-0760(96)00164-1

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 μM 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 IC 50 of ∼28 μM. 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.