title: Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy.
abstract: 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.
authors.affiliation: TAP Pharmaceutical Products Inc., 675 N. Field Drive, Lake Forest, IL 600452, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: DeManno
authors.forename: Walter
authors.initials: W
authors.lastname: Elger
authors.forename: Ramesh
authors.initials: R
authors.lastname: Garg
authors.forename: Ronald
authors.initials: R
authors.lastname: Lee
authors.forename: Birgitt
authors.initials: B
authors.lastname: Schneider
authors.forename: Holger
authors.initials: H
authors.lastname: Hess-Stumpp
authors.forename: Gerd
authors.initials: G
authors.lastname: Schubert
authors.forename: Kristof
authors.initials: K
authors.lastname: Chwalisz
mesh_terms: D000818:Animals; D004715:Endometriosis / Q000188:drug therapy; D004717:Endometrium / Q000187:drug effects; D004963:Estrenes; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D008956:Models, Chemical; D010091:Oximes / Q000494:pharmacology*; D010120:Oxytocics / Q000494:pharmacology*; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*
chemical_list: D004963:Estrenes; D008024:Ligands; D010091:Oximes; D010120:Oxytocics; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; C488516:asoprisnil