Discovery and biological characterization of a novel series of androgen receptor modulators.
OBJECTIVE
Selective androgen receptor modulators are of great value in the treatment of prostate cancer. The purpose of this study was to provide a preliminary characterization of a new class of non-steroidal androgen receptor modulators discovered in a high-throughput screening campaign.


METHODS
Competitive receptor binding, luciferase-based reporter methods, cell proliferation and in vivo assays were employed to evaluate an initial set of compounds from chemistry efforts.


RESULTS
Forty-nine analogues from the chemistry efforts showed high affinity binding to androgen receptors, agonist and/or antagonist activities in both CV-1 and MDA-MB-453 transfection assays. A proliferation assay in LNCaP cells also exhibited this profile. A representative of these non-steroidal compounds (compound 21) was devoid of activity at other nuclear receptors (oestrogen, progesterone, glucocorticoid and mineralocorticoid receptors) in the CV-1 co-transfection assay. At the same time, in an immature castrated rat model, it behaved as an androgen receptor antagonist against the growth of prostate, seminal vesicles and levator ani induced by exogenous androgen. Separation of compound 21 into its enantiomers showed that nearly all the androgen receptor modulating activity and binding resided in the dextrorotatory compound (23) while the laevorotatory isomer (22) possessed weak or little effect depending on the cell type studied.


CONCLUSIONS
These non-steroidal compounds may represent a new class of androgen receptor modulators for the treatment of not only prostate cancer but other clinical conditions where androgens and androgen receptors are involved in the pathological processes.
Zhou
C
C
The National Center for Drug Screening and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Wu
G
G
Feng
Y
Y
Li
Q
Q
Su
H
H
Mais
D E
DE
Zhu
Y
Y
Li
N
N
Deng
Y
Y
Yang
D
D
Wang
M-W
MW
D000726:Androgen Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000494:pharmacology; D009919:Orchiectomy; D010865:Pilot Projects; D011467:Prostate / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012669:Seminal Vesicles / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D011944:Receptors, Androgen; D054852:Small Molecule Libraries; D014105:Tosyl Compounds; D013739:Testosterone; C053541:bicalutamide