Experimental studies on the endocrine side effects of new aldosterone antagonists.
In the present study, endocrine-pharmacological profiles of new aldosterone antagonists, 15 beta,16 beta-methylenemexrenone (ZK 91587), delta 1-15 beta,16 beta-methylene-spironolactone (mespirenone, ZK 94679) and 7 alpha-thiomethyl analogue of mespirenone (ZK 97894) were characterized in comparing them with those of spironolactone. The results obtained indicate that all three compounds are distinctly less antiandrogenic than spironolactone in inhibiting the testosterone-induced organ growth of seminal vesicles and prostates in orchidectomized rats. The weak antiandrogenic activity of ZK 91587 and mespirenone is also manifested in the intrauterine feminizing effect on rat male foetuses. The in vitro study demonstrates that spironolactone and mespirenone inhibit the human chorionic gonadotropin-stimulated testosterone biosynthesis by rat testis cells, but that ZK 91587 and ZK 97894 have no appreciable effect on it. By contrast, the luteinizing hormone (LH)-dependent testosterone biosynthesis by mouse Leydig's cells is suppressed by ZK 97894, but not by spironolactone, mespirenone or ZK 91587. Mespirenone and spironolactone, given subcutaneously, show the same progestogenic potency in estrogen-primed ovariectomized rabbits. ZK 91587 and ZK 97894 are, however, less progestogenic than spironolactone, when administered subcutaneously. On oral administration, mespirenone and ZK 97894 show 2 to 3 times the progestogenic potency of spironolactone. Mesporenone causes a decrease in the serum testosterone and LH levels in cynomolgus monkeys and is about 2 times as potent as spironolactone. These results suggest that mespirenone seems to be a suitable candidate for development as a clinically useful aldosterone antagonist.
Nishino
Y
Y
Research Laboratories of Schering Aktiengesellschaft, Berlin (West), Fed. Rep. of Germany.
Schröder
H
H
el Etreby
M F
MF
D000726:Androgen Antagonists; D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004700:Endocrine System Diseases / Q000139:chemically induced*; D007986:Luteinizing Hormone / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000009:adverse effects*; D011374:Progesterone / Q000096:biosynthesis; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013148:Spironolactone / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D013739:Testosterone / Q000096:biosynthesis
D000726:Androgen Antagonists; D006063:Chorionic Gonadotropin; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D013739:Testosterone; D011374:Progesterone; C054537:ZK 91587; D007986:Luteinizing Hormone; C058243:ZK 97894; C051308:mespirenone