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.