New analogues of mifepristone with more dissociated antiprogesterone activities.
Mifepristone (RU 486 or RU 38486) possesses strong antiprogesterone and antiglucocorticoid along with moderate antiandrogen properties, which would limit its use in some therapeutic applications. In a search for more dissociated derivatives, the hydroxy substituent and the propynyl group in position 17 of the RU 486 series was replaced by a spiroether group, which is known to induce specific affinity for the progestin receptor in steroid series. The substituents in the para position of the 11 beta-phenyl group, leading to the most potent derivatives in the RU 486 series, were retained. The new derivatives have been studied in vitro for their relative binding affinities (RBAs) for the steroid receptor and in vivo for their hormonal and antihormonal activities. The selected compounds, RU 46556 and RU 49295 display the following properties: in vitro, like RU 486, they show a strong RBA for the rabbit progestin receptor, but a much lower one for the rat thymus glucocorticoid receptor; in vivo they are about three times more active than RU 486 for inducing abortion in rats, but unlike the latter they are devoid of any antiglucocorticoid activity on the thymus weight in rats. These antiprogesterone effects have been confirmed on the deciduoma formation in rats and on the endometrial proliferation in rabbits. However, in contrast to RU 486 in the latter test, some progestomimetic activity has been observed. RU 46556 and RU 49295 are now under extensive pharmacological study.
Philibert
D
D
Centre de Recherches Roussel-Uclaf, Romainville, France.
Hardy
M
M
Gaillard-Moguilewsky
M
M
Nique
F
F
Tournemine
C
C
Nédélec
L
L
D000019:Abortifacient Agents; D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D005260:Female; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D008297:Male; D015735:Mifepristone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D010052:Ovariectomy; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship
D000019:Abortifacient Agents; D006727:Hormone Antagonists; D007202:Indicators and Reagents; D015735:Mifepristone; D011374:Progesterone; D000324:Adrenocorticotropic Hormone