Gerd Schubert

Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy

Asoprisnil is a novel selective steroid receptor modulator that shows unique pharmacodynamic effects in animal models and humans. Asoprisnil, its major metabolite J912, and structurally related compounds represent a new class of progesterone receptor (PR) ligands that exhibit partial agonist and antagonist activities in vivo. Asoprisnil demonstrates a high degree of receptor and tissue selectivity, with high-binding affinity for PR, moderate affinity for glucocorticoid receptor (GR), low affinity for androgen receptor (AR), and no binding affinity for estrogen or mineralocorticoid receptors. In the rabbit endometrium, both asoprisnil and J912 induce partial agonist and antagonist effects. Asoprisnil induces mucification of the guinea pig vagina and has pronounced anti-uterotrophic effects in normal and ovariectomized guinea pigs. Unlike antiprogestins, asoprisnil shows only marginal labor-inducing activity during mid-pregnancy and is completely ineffective in inducing preterm parturition in the guinea pig. Asoprisnil exhibits only marginal antiglucocorticoid activity in transactivation in vitro assays and animal models. In male rats, asoprisnil showed weak androgenic and anti-androgenic properties. In toxicological studies in female cynomolgus monkeys, asoprisnil treatment abolished menstrual cyclicity and endometrial atrophy. Early clinical studies of asoprisnil in normal volunteers demonstrated a dose-dependent suppression of menstruation irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no antiglucocorticoid effects. Unlike progestins, asoprisnil does not induce breakthrough bleeding. With favorable safety and tolerability profiles thus far, asoprisnil appears promising as a novel treatment of gynecological disorders, such as uterine fibroids and endometriosis.

Selective Progesterone Receptor Modulators (SPRMs)

Abstract: Endometriosis, the presence of endometrial tissue outside the uterus, is a progressive, estrogen‐dependent disease and occurs nearly exclusively in menstruating women of reproductive age. Pain syndrome, however, represents the major clinical problem of this disease, manifested as dysmenorrhea, pelvic pain, lower abdominal pain, and dyspareunia. The manifestation of the disease, that is, the pain syndrome, rather than the disease itself currently represents the major indication for both the medical and surgical therapies of endometriosis. The major drawbacks of current medical therapies of endometriosis are sometimes severe side effects. In this review, selective progesterone receptor modulators (SPRMs, mesoprogestins) as a potential therapeutic concept in endometriosis are discussed. Due to endometrial selectivity and favorable pharmacological profile, SPRMs may have advantages over the current medical treatments of this disease. Other emerging therapeutic approaches for this disease are also mentioned.