11beta-alkyl-Delta9-19-nortestosterone derivatives: high-affinity ligands and potent partial agonists of the androgen receptor

J Med Chem. 2004 Oct 7;47(21):4985-8. doi: 10.1021/jm0342515.

Abstract

We report the synthesis of novel steroidal androgen receptor ligands comprising 11beta-alkyl-Delta(9)-derivatives of 19-nortestosterone. These compounds are structurally related to the antiprogestin, antiglucocorticoid, and antiandrogen drug mifepristone (RU486). Nortestosterone analogues bearing 11beta-octyl and 11beta-decyl side-chains bind tightly to recombinant AR protein (IC(50) = 6.6 nM and IC(50) = 0.8 nM), block AR dimerization, exhibit activity against LNCaP prostate cancer cells, and comprise partial AR agonists with low antiglucocorticoid activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgen Antagonists / chemical synthesis
  • Androgen Antagonists / pharmacology
  • Androgen Receptor Antagonists
  • Androgens*
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • CHO Cells
  • Cell Line, Tumor
  • Cricetinae
  • Cyproterone Acetate / pharmacology
  • Dimerization
  • Humans
  • Ligands
  • Male
  • Mifepristone / pharmacology
  • Nandrolone / analogs & derivatives*
  • Nandrolone / chemical synthesis*
  • Nandrolone / pharmacology
  • Prostatic Neoplasms
  • Receptors, Androgen / chemistry
  • Structure-Activity Relationship

Substances

  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Androgens
  • Antineoplastic Agents
  • Ligands
  • Receptors, Androgen
  • Mifepristone
  • Cyproterone Acetate
  • Nandrolone