NONSTEROIDAL L-245,976 ACTS AS A CLASSICAL ANTIANDROGEN IN-VITRO

Non-steroidal antiandrogens have been employed in the management of pr ostate cancer, but the mechanism of action is unclear due to a lack of good tissue culture models. The growth of a hamster ductus deferens c ell line (DDT1) is highly dependent upon the addition of 10 nM testost erone to synthetic serum-free media. We describe a non-steroidal compo und chlorophenyl)-(Z,Z)-2,3-bis(-cyclopropylmethylene) cyclopentanecar boxamide (L-245976) which antagonizes the action of testosterone on DD T1 cells at 10 mu M but exhibits little or no effect on cell growth by itself. This compound also blocks the binding of H-3-dihydrotestoster one (DHT) to the human androgen receptor (AR) with an IC50 of similar to 28 mu M. In addition, L-245976 was found to antagonize DHT-dependen t transactivation of the AR via the probasin gene promoter at comparab le doses with no agonist activity. Copyright (C) 1997 Elsevier Science Ltd.