Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist

J Med Chem. 2000 Dec 28;43(26):5010-6. doi: 10.1021/jm001000c.

Abstract

Herein we describe the chemical synthesis and pharmacological characterization of a novel, highly potent progesterone receptor (PR) antagonist, ZK 230211. The introduction of a 17alpha-pentafluorethyl side chain in the D-ring of the steroid skeleton allowed the combination of high antiprogestagenic activity with little or no other endocrinological effects. In contrast to many other antiprogestins, ZK 230211 did not convert to an agonist in the presence of protein kinase A (PKA) activators and showed high antiprogestagenic activity on both PR isoforms PR-A and PR-B. This high antiprogestagenic activity could also be demonstrated in several in vivo models. Furthermore, this compound displayed only marginal antiglucocorticoid effects. In tumor models ZK 230211 exhibited strong antiproliferative action. The pharmacological properties of ZK 230211 may prove useful in the treatment of endometriosis, leiomyomas, breast cancer, and in hormone replacement therapy.

Publication types

  • Comparative Study

MeSH terms

  • Abortifacient Agents / chemical synthesis
  • Abortifacient Agents / metabolism
  • Abortifacient Agents / pharmacology
  • Adrenalectomy
  • Androgen Antagonists / chemical synthesis
  • Androgen Antagonists / metabolism
  • Androgen Antagonists / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Binding, Competitive
  • Castration
  • Cell Line
  • Estrenes / chemical synthesis*
  • Estrenes / metabolism
  • Estrenes / pharmacology
  • Female
  • Glucocorticoids / antagonists & inhibitors
  • Gonanes / pharmacology
  • Hormone Antagonists / chemical synthesis*
  • Hormone Antagonists / metabolism
  • Hormone Antagonists / pharmacology
  • Ligands
  • Male
  • Mammary Neoplasms, Experimental / drug therapy
  • Mifepristone / pharmacology
  • Progesterone / antagonists & inhibitors
  • Progesterone / pharmacology
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Androgen / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Progesterone / antagonists & inhibitors*
  • Receptors, Progesterone / metabolism
  • Transcriptional Activation

Substances

  • Abortifacient Agents
  • Androgen Antagonists
  • Antineoplastic Agents
  • Estrenes
  • Glucocorticoids
  • Gonanes
  • Hormone Antagonists
  • Ligands
  • Protein Isoforms
  • Receptors, Androgen
  • Receptors, Estrogen
  • Receptors, Glucocorticoid
  • Receptors, Progesterone
  • Mifepristone
  • Progesterone
  • lonaprisan
  • onapristone