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

U. Fuhrmann, Fuhrmann U, H Hess-Stumpp, Hess-Stumpp H, A Cleve, Cleve A, G Neef, Neef G, W Schwede, Schwede W, Jens Hoffmann, J Hoffmann, K H Fritzemeier, Fritzemeier KH, K. Chwalisz, Chwalisz K
Journal of medicinal chemistry · 2000 · doi:10.1021/jm001000c · PMID:11150172
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A novel progesterone receptor antagonist, ZK 230211, was synthesized and demonstrated high antiprogestagenic activity with minimal other endocrinological effects and antiproliferative action in tumor models.

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The paper describes the synthesis of a novel, highly potent progesterone receptor antagonist and reports its in vitro antagonist potency using transactivation assays. The antagonist showed very low IC50 values in neuroblastoma cells expressing human progesterone receptor isoforms PR-B (0.0025 nM and 0.025 nM reported) and PR-A (0.0036 nM and 0.028 nM reported). The study also reports reduced potency against other steroid receptors in cell-based transactivation assays, including glucocorticoid receptor and androgen receptor (with IC50 values ranging from about 2.2 nM to 54 nM, depending on receptor and cell line). The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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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.
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Report error Found 8 Enz. Inhib. hit(s) with all data for entry = 50041288 Affinity DataIC50: 0.00250nMAssay Description:In vitro antagonist potency in transactivation assay in neuroblastoma cells expressing human PR-B progesterone receptorMore data for this Ligand-Target Pair Affinity DataIC50: 0.00360nMAssay Description:In vitro antagonist potency in transactivation assay in neuroblastoma cells expressing human PR-A progesterone receptorMore data for this Ligand-Target Pair Affinity DataIC50: 0.0250nMAssay Description:In vitro antagonist potency in transactivation assay in neuroblastoma cells expressing human PR-B progesterone receptorMore data for this Ligand-Target Pair Affinity DataIC50: 0.0280nMAssay Description:In vitro antagonist potency in transactivation assay in neuroblastoma cells expressing human PR-A progesterone receptorMore data for this Ligand-Target Pair Affinity DataIC50: 2.20nMAssay Description:In vitro antagonist potency in transactivation assay in NIH3T3 cells expressing glucocorticoid receptorMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:In vitro antagonist potency in transactivation assay in CV-1 cells expressing androgen receptorMore data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:In vitro antagonist potency in transactivation assay in NIH3T3 cells expressing glucocorticoid receptorMore data for this Ligand-Target Pair Affinity DataIC50: 54nMAssay Description:In vitro antagonist potency in transactivation assay in CV-1 cells expressing androgen receptorMore data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Estrenes Hormone Antagonists Receptors, Progesterone Abortifacient Agents Abortifacient Agents Abortifacient Agents Abortifacient Agents Adrenalectomy Androgen Antagonists Androgen Antagonists Androgen Antagonists Androgen Antagonists Animals Antineoplastic Agents Antineoplastic Agents Antineoplastic Agents Antineoplastic Agents Binding, Competitive Castration Cell Line

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europepmc
last seen: 2026-08-08T06:08:32.324769+00:00
pubmed
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