“…This article discloses preliminary structure−activity relationship studies of a series of nonsteroidal hPR-B antagonists based on the 1,2-dihydro-2,2,4-trimethyl-6-phenylquinoline pharmacophore, 3 . Whereas previous studies of nonsteroidal progesterone receptor antagonists have failed to demonstrate oral activity in vivo, , two of the novel antiprogestins presented here have definitive anti-progestational effects when dosed orally to rodents. 1 Mifepristone ( 1 ), onapristone ( 2 ), and LG001447 ( 3 ).…”
Section: Introductionmentioning
confidence: 54%
“…We have been engaged in the discovery of nonsteroidal progesterone receptor modulators . To date there have been few classes of nonsteroidal progesterone receptor modulators reported, and none have reached the clinic, although steroidal hPR antagonists, typified by mifepristone ( 1 , RU486) and onapristone ( 2 , ZK98,299), have been studied clinically. The potential uses for antiprogestins include therapies for various gynecological diseases, and nonsteroidal antiprogestins might be expected to display novel pharmacology …”
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.
“…This article discloses preliminary structure−activity relationship studies of a series of nonsteroidal hPR-B antagonists based on the 1,2-dihydro-2,2,4-trimethyl-6-phenylquinoline pharmacophore, 3 . Whereas previous studies of nonsteroidal progesterone receptor antagonists have failed to demonstrate oral activity in vivo, , two of the novel antiprogestins presented here have definitive anti-progestational effects when dosed orally to rodents. 1 Mifepristone ( 1 ), onapristone ( 2 ), and LG001447 ( 3 ).…”
Section: Introductionmentioning
confidence: 54%
“…We have been engaged in the discovery of nonsteroidal progesterone receptor modulators . To date there have been few classes of nonsteroidal progesterone receptor modulators reported, and none have reached the clinic, although steroidal hPR antagonists, typified by mifepristone ( 1 , RU486) and onapristone ( 2 , ZK98,299), have been studied clinically. The potential uses for antiprogestins include therapies for various gynecological diseases, and nonsteroidal antiprogestins might be expected to display novel pharmacology …”
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.
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