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 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) was discovered via directed high throughput screening of a defined chemical library utilizing an hPR-B cotransfection assay. Electron-withdrawing substituents at the meta position of the C(6) aryl group afforded substantial improvements in hPR modulatory activity. Several analogues were able to potently 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. This is the first disclosure of orally active nonsteroidal antiprogestins.
Department of Medicinal Chemistry, Ligand Pharmaceuticals Inc., San Diego, California 92121, USA. cdeckhut@ligand.com
C L
CL
Pooley
J P
JP
Edwards
M E
ME
Goldman
M W
MW
Wang
K B
KB
Marschke
D L
DL
Crombie
T K
TK
Jones
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D002521:Cercopithecus; D010064:Embryo Implantation / Q000187:drug effects; D005260:Female; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011247:Pregnancy; D011804:Quinolines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D006067:Gonanes; D006727:Hormone Antagonists; C114192:LG 120753; C114191:LG 120830; D011804:Quinolines; D011980:Receptors, Progesterone; C053238:onapristone