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.

Gynaecological uses of a new class of steroids: the selective progesterone receptor modulators

“…All doses were significantly effective on pain scores, at all treatment months compared with placebo [70]. The effect on bleeding pattern was also dose-dependent.…”

“…No decrease of plasma estradiol or increase of cortisol was observed. This treatment is well tolerated and reduces significantly both duration and intensity of uterine bleeding in a dose-dependant manner [70].…”

“…The primary action of progesterone is to initiate and maintain pregnancy. Progesterone, the natural ligand of the PR, represents the pure agonist, onapristone, mifepristone show a pure antagonist activity and asoprisnil exhibits partial agonist/antagonist effects [1].The synthesis of mifepristone, the first PR antagonist (PA) was a starting point of drug discovery and the research programme in the area of PAs [2][3][4].…”

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

“…Whilst the results of this study were reported as an abstract only, a significant decrease in daily pain scores with all doses of asoprisnil (5, 10 or 25 mg) compared with placebo was noted (Chwalisz et al, 2005b). Intriguing as these data are, there has been a compelling lack of replication studies from double blinded, randomised and controlled trials in women with endometriosis, using empirical and objective outcome measures approved by regulatory bodies.…”

Non-monotonic dose–response relationship in steroid hormone receptor-mediated gene expression

“…For example, tamoxifen and raloxifene are selective ER modulators, which are antiestrogenic in the breast but estrogenic in the bone (Dutertre & Smith 2000, Francucci et al 2005. Asoprisnil, a selective PR modulator, has an antiproliferative effect on primate endometrium, but cannot induce labor in animal models of pregnancy and parturition (Chwalisz et al 2005). Current understanding of the molecular mechanism for tissue-selective action of SRMs hinges on the notion that SRMs can induce different conformational changes to their cognate SHRs, particularly in the C-terminal LBD, which in turn determine whether CoA or CoR will be recruited (Brzozowski et al 1997, Shiau et al 1998.…”