DISCOVERY AND PRELIMINARY SAR STUDIES OF A NOVEL, NONSTEROIDAL PROGESTERONE-RECEPTOR ANTAGONIST PHARMACOPHORE

A series of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines was synthesiz ed and tested for functional activity on the human progesterone recept or isoform B (hPR-B) in mammalian (CV-1) cells. The lead compound LG00 1447 (1,2-dihydro-2,2,4-trimethyl-6-phenylquinoline) was discovered vi a directed high throughput screening of a defined chemical library uti lizing an hPR-B cotransfection assay. Electron-withdrawing substituent s at the meta position of the C(6) aryl group afforded substantial imp rovements in hPR modulatory activity. Several analogues were able to p otently block the effects of progesterone in vitro. Two compounds, 10 (LG120753) and 11 (LG120830) with potencies comparable or equal to the steroidal hPR antagonist onapristone (ZK98,299), were demonstrated to act as antiprogestins in vivo after oral administration to rodents. T his is the first disclosure of orally active nonsteroidal antiprogesti ns.