ABSTRACT

Antiprogestins can be used for a variety of clinical indications. These include clinical use for pregnancy interruption, labor management and anticonception. Besides these applications, antiprogestins can be used for the treatment of endometriosis, uterine leio-myomata, breast tumors and meningiomas.

The antiprogestins act via the progesterone receptor (PR) isoforms, for which distribution and expression are differently regulated among the various reproduction associated tissues. The pivotal role of PR for female reproduction has become clear with PR (A and B) and specific PR-A knock-out mice, which are infertile. The mechanism of action of antiprogestins through PR-A and -B depends on the PR-A/B ratio, the cellular and promoter context, the presence of protein kinase A activity, and the presence of co-activators and co-repressors. Finally the molecular structure of the antiprogestins themselves has a strong impact.

RU 38486 (RU 486, mifepristone), a 19-norsteroid with an 11ß-(4-dimethylamino) (amino) phenyl and a 17α- propynyl side chain, was the first potent antiprogestin identified. Its antagonistic bioactivity was shown in pregnancy interruption and anti-McPhail tests. Unfortunately, RU 486 has also an antiglucocorticoid activity. Improvement of this antiprogestagenic/ antigluco-corticoid selectivity is required to reduce its adverse side effects. To achieve this goal new antiprogestins are still in development.

In this review the pharmacological profile of several newly developed antiprogestins is compared with five standards, i.e. RU 486, ZK 98299, ZK 112993, Org 31710 and Org 31806, using different tests. On the molecular level, in vitro studies can discriminate between ligand-receptor, reporter assays, receptor- DNA, and cellular responses. Thereto receptor binding, receptor mediated transactivation, gel retardation and inhibition of breast tumor cell growth studies were carried out, respectively. With respect to in vivo studies, three animal models exist for endometrium, i.e. pregnancy interruption, endometrium proliferation and menses induction, while breast tumor prevention can be seen as a beneficial effect for antiprogestins. Adverse effects for antiglucocorticoid in vivo activity are measured on thymus, adrenal and body weight reduction and with in vitro binding and transactivation studies. All antiprogestins were tested in binding, transactivation, pregnancy interruption and endometrium proliferation tests. The most potent compounds were selected for in vitro and in vivo  antiglucocortioid activity measurements. This complex set of assays is carried out to get a clear profile of the compounds and to make a proper selection taking data from all these assays into account. The four selected antiprogestins combine a 17-(5)-spiromethylene ether group with an 11ß-(4-dimethylamino)phenyl (Org  33245), 11 ß-(4-acetyl)phenyl (Org 33628), (4-methylthio)phenyl (Org 33832) or (4-methoxy)phenyl (Org 33901) group and appeared to be among the most potent representatives of 38 different antiprogestins tested, standards included. Since Org 33245, Org 33628 and/or Org 33832 were more active in pregnancy interruption and menses induction tests than Org 33901, these compounds are considered for further evaluation. Org 33628 has been selected for further clinical development.