Discovery and Preliminary SAR Studies of a Novel, Nonsteroidal Progesterone Receptor Antagonist Pharmacophore

摘要: A series of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines was synthesized and tested for functional activity on the human progesterone receptor isoform B (hPR-B) in mammalian (CV-1) cells. The lead compound LG001447 (1,2-dihydro-2,2,4-trimethyl-6-phenylquinoline) discovered via directed high throughput screening a defined chemical library utilizing an hPR-B cotransfection assay. Electron-withdrawing substituents at meta position C(6) aryl group afforded substantial improvements hPR modulatory activity. Several analogues were able to potently block effects vitro. Two compounds, 10 (LG120753) 11 (LG120830) with potencies comparable or equal steroidal antagonist onapristone (ZK98,299), demonstrated act as antiprogestins vivo after oral administration rodents. This is first disclosure orally active nonsteroidal antiprogestins.