27 - 30 May 2005

ZK PR-A: A UTERUS-SELECTIVE NONSTEROIDAL PR MODULATOR Fuhrmann U [*], Prelle K [*], Hegele-Hartung Ch[**], Kettschau G [+], Lehmann M [+], Klotzbücher M [o], Muhn P[*], Wortmann L [+] [*] Schering AG, Female Health Care Research [**] Schering AG, Safety Pharmacology [+] Schering AG, Medicinal Chemistry [o] Schering AG, Marketing Gynaecology& Andrology

The biological response to progesterone is mediated by two distinct isoforms of the progesterone receptor, PR-A and PR-B, arising from the same gene. PR-A and PR-B are identical except for 164 additional N-terminal amino acids unique to PR-B. Both PR-isoforms are expressed in all progesterone target organs tested so far (e.g. breast, uterus). However, there is strong evidence that PR-A and PR-B function in a tissue-specific manner to mediate responses to progesterone.

Isoform-specific knock-out mice show different functions of PR-A and PR-B in the same target organ. Based on these studies PR-B seems to be responsible for mediating progestogenic effects on mammary gland proliferation and differentiation, whereas the antiproliferative action of progestins on the uterine epithelium is most likely mediated by PR-A.

We could identify a PR-A specific ligand with the following pharmacological profile: ZK PR-A is a highly potent nonsteroidal PR modulator that transactivates the A isoform of PR with higher efficacy than the B isoform. ZK PR-A exhibits high potency in the uterus as could be shown in several assays for progestogenic activity in vivo. Furthermore, ZK PR-A has been shown to be a tissue-specific PR modulator with a strong effect on the uterus and a dissociation regarding effects on uterine versus breast tissue and the ovary.

Finally, ZK PR-A is PR specific being devoid of activities mediated by other members of the steroid receptor family in vivo. Because of this special pharmacological profile ZK PR-A is a highly suitable compound for fertility control and hormone therapy.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract