title: Antiandrogenic steroidal sulfonylpyrazoles.
abstract: 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.
authors.affiliation: Department of Chemistry, Sterling Research Group, Rensselaer, New York 12144.
authors.forename: R G
authors.initials: RG
authors.lastname: Christiansen
authors.forename: M R
authors.initials: MR
authors.lastname: Bell
authors.forename: T E
authors.initials: TE
authors.lastname: D'Ambra
authors.forename: J P
authors.initials: JP
authors.lastname: Mallamo
authors.forename: J L
authors.initials: JL
authors.lastname: Herrmann
authors.forename: J H
authors.initials: JH
authors.lastname: Ackerman
authors.forename: C J
authors.initials: CJ
authors.lastname: Opalka
authors.forename: R K
authors.initials: RK
authors.lastname: Kullnig
authors.forename: R C
authors.initials: RC
authors.lastname: Winneker
authors.forename: B W
authors.initials: BW
authors.lastname: Snyder
mesh_terms: 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
chemical_list: D000726:Androgen Antagonists; D011278:Pregnanes; D011720:Pyrazoles; D011944:Receptors, Androgen; D013739:Testosterone; C060492:zanoterone