title: Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridono[5,6-g]quinolines.
abstract: A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure-activity relationships surrounding this pharmacophore resulted in molecules 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 potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.
authors.affiliation: Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA. lhamann@ligand.com
authors.forename: L G
authors.initials: LG
authors.lastname: Hamann
authors.forename: R I
authors.initials: RI
authors.lastname: Higuchi
authors.forename: L
authors.initials: L
authors.lastname: Zhi
authors.forename: J P
authors.initials: JP
authors.lastname: Edwards
authors.forename: X N
authors.initials: XN
authors.lastname: Wang
authors.forename: K B
authors.initials: KB
authors.lastname: Marschke
authors.forename: J W
authors.initials: JW
authors.lastname: Kong
authors.forename: L J
authors.initials: LJ
authors.lastname: Farmer
authors.forename: T K
authors.initials: TK
authors.lastname: Jones
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D006062:Gonadotropins / Q000097:blood; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D015394:Molecular Structure; D009919:Orchiectomy; D011467:Prostate / Q000187:drug effects / Q000254:growth & development; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012669:Seminal Vesicles / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000097:blood; D014162:Transfection
chemical_list: C110821:1,2-dihydropyridono(5,6-g)quinoline; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D004095:Dihydropyridines; D006062:Gonadotropins; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D011804:Quinolines; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D013196:Dihydrotestosterone; D013739:Testosterone