A novel class of nonsteroidal progesterone receptor antagonists has been synthesized and was shown to exhibit moderate binding affinity for hPR-A, the ability to inhibit the transcriptional activity of human progesterone receptor (hPR) in cell-based assays, and anti-progestational activity in a murine model. Cyclocymopol monomethyl ether, a component of the marine alga Cymopolia barbata was weakly active in random screening against PR. Investigations into the SAR surrounding the core of this natural product lead structure resulted in improved in vitro activity. In contrast to the cross-reactivity profiles observed with known steroidal anti-progestins, compounds of the general structural class described display a high degree of selectivity for the progesterone receptor and no functional activity on the glucocorticoid receptor.