Selective Progesterone Receptor Modulator Development and Use in the Treatment of Leiomyomata and Endometriosis
Kristof Chwalisz,
Maria Claudia Perez,
Deborah DeManno,
Craig Winkel,
Gerd Schubert and
Walter Elger
TAP Pharmaceutical Products, Inc. (K.C., M.C.P., D.D.), Lake Forest, Illinois 60045; School of Nursing (C.W.), Georgetown University, Washington, D.C. 20007; Jenapharm GmbH & Co. (G.S.), 07745 Jena, Germany; and EnTec GmbH (W.E.), 07745 Jena, Germany
Correspondence: Address all correspondence and requests for reprints to: Kristof Chwalisz, M.D., Ph.D., TAP Pharmaceutical Products, Inc., 675 North Field Drive, Lake Forest, Illinois 60045. E-mail: Kristof.Chwalisz{at}TAP.com
Selective progesterone receptor modulators (SPRMs) representa new class of progesterone receptor ligands. SPRMs exert clinicallyrelevant tissue-selective progesterone agonist, antagonist,or mixed agonist/antagonist effects on various progesteronetarget tissues in vivo. Asoprisnil (J867) is the first SPRMto reach an advanced stage of clinical development for the treatmentof symptomatic uterine fibroids and endometriosis. Asoprisnilbelongs to the class of 11ß-benzaldoxime-substitutedestratrienes that exhibit partial progesterone agonist/antagonisteffects with high progesterone receptor specificity in animalsand humans. Asoprisnil has no antiglucocorticoid activity inhumans at therapeutic doses. It exhibits endometrial antiproliferativeeffects on the endometrium and breast in primates. Unlike progesteroneantagonists, asoprisnil does not induce labor in relevant modelsof pregnancy and parturition. It induces amenorrhea primarilyby targeting the endometrium. In human subjects with uterinefibroids, asoprisnil suppressed both the duration and intensityof uterine bleeding in a dose-dependent manner and reduced tumorvolume in the absence of estrogen deprivation. In subjects withendometriosis, asoprisnil was effective in reducing nonmenstrualpain and dysmenorrhea. Asoprisnil may, therefore, provide anovel, tissue-selective approach to control endometriosis-relatedpain. SPRMs have the potential to become a novel treatment ofuterine fibroids and endometriosis.
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