SYNTHESIS AND BIOLOGICAL-ACTIVITY OF A NOVEL SERIES OF NONSTEROIDAL, PERIPHERALLY SELECTIVE ANDROGEN RECEPTOR ANTAGONISTS DERIVED FROM 1,2-DIHYDROPYRIDONO[5,6-G] QUINOLINES

A new nonsteroidal antiandrogenic pharmacophore has been discovered us ing cell-based cotransfection assays with human androgen receptor (hAR ). This series of AR antagonists is structurally characterized by a li near tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inh ibit AR-mediated reporter gene expression and bind to AR as potently a s or better than any known AR antagonists. Several analogues also show ed excellent in vivo activity in classic rodent models of AR antagonis m, inhibiting growth of rat ventral prostate and seminal vesicles, wit hout accompanying increases in serum gonadotropin and testosterone lev els, as is seen with other AR antagonists. investigations of structure -activity relationships surrounding this pharmacophore resulted in mol ecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the po tential to provide unique and effective clinical opportunities for tre atment of prostate cancer and other androgen-dependent diseases.