Antiandrogenic steroidal sulfonylpyrazoles.
The steroidal sulfonylpyrazole 1 bound to the rat ventral prostate androgen receptor in vitro; it inhibited testosterone propionate induced increases in ventral prostate weight in vivo in the castrated, immature male rat with an ED50 of 15 mg/kg po. Compound 1 lacked androgenic activity in vivo in contrast to the parent steroidal pyrazole 5, which was both androgenic and antiandrogenic. The 2'- and 5'-methylsulfonyl isomers 6 and 6a did not bind to the androgen receptor. Introduction of an alkylsulfonyl at the N-1'-position has served, therefore, to isolate the intrinsic antiandrogenic properties of the steroidal heterocycle free of apparent hormone agonist properties. Structure-activity relationship studies revealed that a methylsulfonyl group at N-1' together with a C-17 alpha-substituent were the optimal combination for in vitro androgen receptor binding, in vivo antiandrogenic potency, and a lack of androgenic activity.
Christiansen
R G
RG
Department of Chemistry, Sterling Research Group, Rensselaer, New York 12144.
Bell
M R
MR
D'Ambra
T E
TE
Mallamo
J P
JP
Herrmann
J L
JL
Ackerman
J H
JH
Opalka
C J
CJ
Kullnig
R K
RK
Winneker
R C
RC
Snyder
B W
BW
D000726:Androgen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D008297:Male; D015394:Molecular Structure; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011278:Pregnanes / Q000378:metabolism / Q000494:pharmacology*; D011467:Prostate / Q000033:anatomy & histology / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011944:Receptors, Androgen / Q000378:metabolism; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000494:pharmacology; D014961:X-Ray Diffraction
D000726:Androgen Antagonists; D011278:Pregnanes; D011720:Pyrazoles; D011944:Receptors, Androgen; D013739:Testosterone; C060492:zanoterone