Klaus Stöckemann

Mechanism of Action of Antiprogestins in the Pregnant Uterus

Progesterone plays a crucial role in nearly the entire female reproductive process in mammals. It most likely controls the final stages of folliculogenesis and regulates ovulation. In addition, progesterone stimulates epithelial proliferation in the mammary gland and controls lactogenesis. During the preimplantation phase of the fertile cycle it prepares the endometrium for implantation by inducing endometrial receptivity. The sudden withdrawal of progesterone action at the end of the luteal phase leads to a constriction of spiral arteries and in turn induces menstruation in primates. During early pregnancy, progesterone is essential for the entire implantation process. In more advanced stages progesterone is responsible for pregnancy maintenance, acting predominantly on the myometrium and the uterine cervix. In addition, there is some evidence that progesterone has an immunosuppressive effect and may regulate the cytokine network in the uterus. Finally, progesterone may play an important role in the maternal adaptation of the cardiovascular system during pregnancy. During the preimplantation period and early pregnancy progesterone targets the endometrium. During later stages of pregnancy the myometrium and the uterine cervix become the major targets. There is ample evidence that during advanced pregnancy progesterone predominantly controls myometrial responsiveness by suppressing both the excitability and the propagation of the uterine muscle. The second important function of progesterone is the control of cervical ripening. Progesterone functions during preg-

Synthesis and biological activity of 17-chloro-16(17) unsaturated D-homo antiprogestins

An efficient approach to 17-chloro-16(17) unsaturated D-homo antiprogestins is described. The key steps of the synthesis are a ring-expansion via dichlorocarbene addition to a 17-silyl enol ether and a palladium catalyzed coupling of an 11 beta-(4-aryltriflate) with tributyl(1-ethoxyethenyl)stannane or diethyl(3-pyridinyl)-borane. The new progesterone antagonists were tested for their biological activities and compared to those of known antiprogestins.