Molecular identification of steroid analogs with dissociated antiprogestin activities.
Antiprogestins of the 11 beta-aryl-substituted 19-norsteroid family are effectively used in inhibiting nidation and in terminating pregnancies. They are potentially useful in the treatment of progesterone-related diseases such as meningiomas and endometriosis and in inhibiting the growth of mammary tumors. However their long-term use is limited because of their inherent antiglucocorticoid activity. Here we have used molecular biological techniques to examine the antiglucocorticoid activity of a series of antiprogestins. The compounds we have analyzed contain different substituents at the C-17 position and a change from the trans to cis configuration of the C-D steroid rings. Our results show that minor changes at the C-17 position but not in the configuration of the C and D rings produced antiprogestins with reduced antiglucocorticoid activity. Thus only subtle changes in the structure of classical antiprogestins are needed for the reduction of their antiglucocorticoid activities.
Wehle
H
H
Kernforschungszentrum Karlsruhe, Institute of Genetics, Germany.
Moll
J
J
Cato
A C
AC
D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006727:Hormone Antagonists / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009654:Norsteroids / Q000737:chemistry* / Q000494:pharmacology*; D011372:Progestins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014162:Transfection
D059002:Androgen Receptor Antagonists; D000728:Androgens; D005938:Glucocorticoids; D006727:Hormone Antagonists; D009654:Norsteroids; D011372:Progestins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins