Antiandrogenic steroidal sulfonylpyrazoles

J Med Chem. 1990 Aug;33(8):2094-100. doi: 10.1021/jm00170a008.

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.

MeSH terms

  • Androgen Antagonists / metabolism
  • Androgen Antagonists / pharmacology*
  • Animals
  • Male
  • Molecular Structure
  • Orchiectomy
  • Organ Size / drug effects
  • Pregnanes / metabolism
  • Pregnanes / pharmacology*
  • Prostate / anatomy & histology
  • Prostate / metabolism
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Androgen / metabolism
  • Structure-Activity Relationship
  • Testosterone / pharmacology
  • X-Ray Diffraction

Substances

  • Androgen Antagonists
  • Pregnanes
  • Pyrazoles
  • Receptors, Androgen
  • Testosterone
  • zanoterone