History and perspectives of antiprogestins from the chemist's point of view.

The discovery of RU486 and its potent activity as an antiglucocorticoid and antiprogestin brought the long story on steroid hormones and antihormones to its logical conclusion. Even though scattered improvements are still possible, the armamentarium of the steroid endocrinologist is by now complete. Like any successful drug, RU486 has become the prototype of a number of analogues which are claimed to be either more active or more dissociated. The literature (mainly patients) has been searched for available data on abortive activities, and some as yet unpublished results on RU compounds have been included. It appears that a number of compounds are both more active than RU486 on a dose basis in animal studies and more dissociated in relation to a possible antiglucocorticoid activity. In addition, hydrosoluble compounds suitable for i.v. injection are available for possible development. In a longer term perspective, it cannot be excluded that potential non-steroidal antiprogestins could present additional advantages over steroidal compounds, in particular improved receptor specificity and/or reduced susceptibility to receptor mutation.