title: Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist.
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.
authors.affiliation: Schering AG, Research Laboratories, D-13342 Berlin, Germany, and Jenapharm, Research Laboratories, D-07745 Jena, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Fuhrmann
authors.forename: H
authors.initials: H
authors.lastname: Hess-Stumpp
authors.forename: A
authors.initials: A
authors.lastname: Cleve
authors.forename: G
authors.initials: G
authors.lastname: Neef
authors.forename: W
authors.initials: W
authors.lastname: Schwede
authors.forename: J
authors.initials: J
authors.lastname: Hoffmann
authors.forename: K H
authors.initials: KH
authors.lastname: Fritzemeier
authors.forename: K
authors.initials: K
authors.lastname: Chwalisz
mesh_terms: D000019:Abortifacient Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000315:Adrenalectomy; D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002369:Castration; D002460:Cell Line; D004963:Estrenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D015735:Mifepristone / Q000494:pharmacology; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015533:Transcriptional Activation; D005466:Fluorocarbons
chemical_list: D000019:Abortifacient Agents; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D004963:Estrenes; D005938:Glucocorticoids; D006067:Gonanes; D006727:Hormone Antagonists; D008024:Ligands; D015735:Mifepristone; D011374:Progesterone; D020033:Protein Isoforms; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; C419162:lonaprisan; D005466:Fluorocarbons; C053238:onapristone