EFFECTS OF D-RING SUBSTITUENTS ON ANTIPROGESTATIONAL (ANTAGONIST) ANDPROGESTATIONAL (AGONIST) ACTIVITY OF 11-BETA-ARYL STEROIDS

The discovery of antiprogestational steroids by the Roussel-Uclaf grou p not only was a major scientific advance but also opened the way to n ew methods of fertility control and new therapies for such conditions as cancer. RU486, the prototype of the series, is distinguished by a p -(N,N-dimethylaminophenyl) substituent at the 11 beta- position of the steroid framework, a 4,9-dien-3-one system and 17 beta-hydroxy-17 alp ha-propynyl substituents. We examined the effect of varying the 17 alp ha- substituent in 17 beta-hydroxy compounds analogous to RU486, the e ffect of introducing a progesterone side chain at C-17, and the effect s of further substitution at C-17 alpha and C-16 alpha on the activity of these latter compounds. These studies indicate an important role f or D-ring substituents in determining the balance of agonist/antagonis t activity in this series. For example, 17 alpha-acetoxy-17 beta-acety l substitution gave a potent antagonist, whereas 16 alpha-ethyl-17 bet a-acetyl substitution resulted in a compound with potent progestationa l (agonist) activity. The compounds present opportunities for further interesting and useful biological investigations.