Rolf Krattenmacher

The novel progestin drospirenone and its natural counterpart progesterone: Biochemical profile and antiandrogenic potential

Drospirenone is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. This specific pharmacological profile of drospirenone is defined by its pattern of binding affinities to a variety of steroid hormone receptors. In the present study the affinity of drospirenone to the progesterone receptor (PR), the androgen receptor (AR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the estrogen receptor (ER) was re-evaluated by steroid binding assays and compared to those obtained for the natural hormone progesterone. Drospirenone displayed high affinity to PR and MR and low binding to AR, similar to progesterone. Unlike progesterone, which showed considerable binding to GR, drospirenone exhibited only low binding to this receptor. Neither drospirenone nor progesterone did bind to the ER. In addition to receptor binding studies, transactivation assays were carried out to investigate the effects of drospirenone and progesterone on AR-, GR-, and MR-mediated induction of transcription. Both progestins showed no androgenic but antiandrogenic activity by inhibiting AR-mediated transcription in a dose-dependent manner. This observation could be confirmed by in vivo experiments carried out with orchiectomized male rats, where the antiandrogenic potency of drospirenone was found to be about five- to ten-fold higher than that of progesterone. In contrast to progesterone, drospirenone was devoid of glucocorticoid activity. Both progestins did not show any antiglucocorticoid action. Furthermore, drospirenone and progesterone both showed considerable antimineralocorticoid activity and weak mineralocorticoid activity.

Drospirenone: a Novel Progestogen with Antimineralocorticoid and Antiandrogenic Activity

Drospirenone (ZK 30595; 6 beta, 7 beta, 15 beta, 16 beta-dimethylen-3-oxo-17 alpha-pregn-4-ene-21, 17-carbolactone) is a novel progestogen under clinical development. Drospirenone is characterized by an innovative pharmacodynamic profile which is very closely related to that of progesterone. Potential applications include oral contraception, hormone replacement therapy and treatment of hormonal disorders. The pharmacological properties of drospirenone were investigated in vitro by receptor binding and transactivation experiments and in vivo in appropriate animal models. In qualitative agreement with progesterone, the compound binds strongly to the progesterone and the mineralocorticoid receptor and with lower affinity to androgen and glucocorticoid receptors. There is no detectable binding to the estrogen receptor. Steroid hormone agonistic and antagonistic activities of progesterone and drospirenone were compared in transactivation experiments. Individual steroid hormone receptors were artificially expressed together with a reporter gene in appropriate cell lines. Both hormones were unable to induce any androgen receptor-mediated agonistic activity. Rather, both progesterone and drospirenone distinctly antagonized androgen-stimulated transcriptional activation. Likewise, both compounds only very weakly activated the mineralocorticoid receptor but showed potent aldosterone antagonistic activity. Drospirenone did not induce glucocorticoid receptor-driven transactivation. Progesterone was a weak agonist in this respect. Drospirenone exerts potent progestogenic and antigonadotropic activity which was studied in various animal species. It efficiently promotes the maintenance of pregnancy in ovariectomized rats, inhibits ovulation in rats and mice and stimulates endometrial transformation in the rabbit. Furthermore, drospirenone shows potent antigonadotropic, i.e., testosterone-lowering activity in male cynomolgus monkeys. The progestogenic potency of drospirenone was found to be in the range of that of norethisterone acetate. The majority of clinically used progestogens are androgenic. Drospirenone, like progesterone, has no androgenic but rather an antiandrogenic effect. This property was demonstrated in castrated, testosterone propionate substituted male rats by a dose-dependent inhibition of accessory sex organ growth (seminal vesicles, prostate). In this model, the potency of drospirenone was about a third that of cyproterone acetate. Drospirenone, like progesterone, shows antimineralocorticoid activity, which causes moderately increased sodium and water excretion. This is an outstanding characteristic which has not been described for any other synthetic progestogen before. Drospirenone is eight to ten times more effective in this respect than spironolactone. The natriuretic effect was demonstrable for at least three weeks upon daily treatment of rats with a dose of 10 mg/animal. Drospirenone is devoid of any estrogenic, glucocorticoid or antiglucocorticoid activity. In summary, drospirenone, like progesterone, combines potent progestogenic with antimineralocorticoid and antiandrogenic activity in a similar dose range.(ABSTRACT TRUNCATED AT 400 WORDS)

Drospirenone : a novel progestogen with antimineralocorticoid and antiandrogenic activity : pharmacological characterization in animal models

Drospirenone (ZK 30595; 6 beta, 7 beta, 15 beta, 16 beta-dimethylen-3- oxo-17 alpha-pregn-4-ene-21, 17-carbo-lactone) is a novel progestogen under clinical development. Potential applications include oral contraception, hormone replacement therapy and treatment of hormonal disorders. Drospirenone is characterized by a pharmacodynamic profile very closely related to that of progesterone. The progestogenic activity of drospirenone has been analysed in a variety of animal models. The compound efficiently promotes the maintenance of pregnancy in rats, inhibits ovulation in rats and stimulates endometrial transformation in the rabbit. Furthermore, drospirenone shows potent antigonadotropic, i.e. testosterone-lowering, activity in male cynomolgus monkeys. The progestogenic potency of drospirenone was found to be in the range of that of norethisterone acetate or cyproterone acetate. Like progesterone, drospirenone has been shown to have an antimineralocorticoid effect in rats and humans. It has now been demonstrated that the compound has a long-lasting natriuretic activity in rats on administration of a daily dose of 10 mg s.c. for three weeks. Under identical conditions, spironolactone, a widely-used antimineralocorticoid, becomes ineffective after the initial treatment phase. Drospirenone exhibits antiandrogenic activity in castrated, testosterone-substituted male rats as shown by dose-dependent inhibition of accessory sex organ growth (prostate, seminal vesicles). In this model, the potency of drospirenone was found to be about one-third that of cyproterone acetate. The compound is devoid of androgenic, estrogenic, glucocorticoid and antiglucocorticoid activity. Possible drug interaction between drospirenone and ethinylestradiol (EE) was also investigated. EE did not interfere with either the progestogenic or the antimineralocorticoid activity of drospirenone. In conclusion, drospirenone represents a novel type of synthetic progestogen since it combines potent progestogenic characteristics with antimineralocorticoid and antiandrogenic activity. Thus, the pharmacological profile of drospirenone is more closely related to that of the natural hormone progesterone than is that of any other synthetic progestogen in use today. Therefore, drospirenone is anticipated to give rise to a number of additional health benefits both for users of oral contraceptives and hormone replacement therapy recipients.

Synthesis and Biological Activity of 11,19-Bridged Progestins

A synthetic approach to 11,19-bridged progestins is described. The key step in the synthesis is a 6-endo-trig radical cyclisation. The new progestins were tested for their biological activities in vitro and in vivo and compared to those of known progestins.