title: Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.
abstract: Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11beta-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroids, asoprisnil suppressed both the duration and intensity of uterine bleeding in a dose-dependent manner and reduced tumor volume in the absence of estrogen deprivation. In subjects with endometriosis, asoprisnil was effective in reducing nonmenstrual pain and dysmenorrhea. Asoprisnil may, therefore, provide a novel, tissue-selective approach to control endometriosis-related pain. SPRMs have the potential to become a novel treatment of uterine fibroids and endometriosis.
authors.affiliation: TAP Pharmaceutical Products, Inc., 675 North Field Drive, Lake Forest, Illinois 60045, USA. Kristof.Chwalisz@TAP.com
authors.forename: Kristof
authors.initials: K
authors.lastname: Chwalisz
authors.forename: Maria Claudia
authors.initials: MC
authors.lastname: Perez
authors.forename: Deborah
authors.initials: D
authors.lastname: Demanno
authors.forename: Craig
authors.initials: C
authors.lastname: Winkel
authors.forename: Gerd
authors.initials: G
authors.lastname: Schubert
authors.forename: Walter
authors.initials: W
authors.lastname: Elger
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D004715:Endometriosis / Q000188:drug therapy*; D004963:Estrenes; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy*; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D010120:Oxytocics / Q000494:pharmacology / Q000627:therapeutic use; D011374:Progesterone / Q000378:metabolism; D011980:Receptors, Progesterone / Q000819:agonists* / Q000037:antagonists & inhibitors*; D014594:Uterine Neoplasms / Q000188:drug therapy*
chemical_list: D004963:Estrenes; D010091:Oximes; D010120:Oxytocics; D011980:Receptors, Progesterone; D011374:Progesterone; C488516:asoprisnil