DeManno Deborah, Elger Walter, Garg Ramesh, Lee Ronald, Schneider Birgitt, Hess-Stumpp Holger, Schubert Gerd, Chwalisz Kristof
TAP Pharmaceutical Products Inc., 675 N. Field Drive, Lake Forest, IL 600452, USA.
Steroids. 2003 Nov;68(10-13):1019-32. doi: 10.1016/j.steroids.2003.09.008.
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.
阿索普瑞尼是一种新型选择性类固醇受体调节剂，在动物模型和人类中显示出独特的药效学作用。阿索普瑞尼、其主要代谢产物J912以及结构相关化合物代表了一类新的孕激素受体（PR）配体，在体内表现出部分激动剂和拮抗剂活性。阿索普瑞尼表现出高度的受体和组织选择性，对PR具有高结合亲和力，对糖皮质激素受体（GR）具有中等亲和力，对雄激素受体（AR）具有低亲和力，对雌激素或盐皮质激素受体无结合亲和力。在兔子宫内膜中，阿索普瑞尼和J912均诱导部分激动剂和拮抗剂作用。阿索普瑞尼诱导豚鼠阴道黏液化，并对正常和去卵巢豚鼠有明显的抗子宫生长作用。与抗孕激素不同，阿索普瑞尼在妊娠中期仅表现出微弱的引产活性，在豚鼠中诱导早产完全无效。阿索普瑞尼在体外转录激活试验和动物模型中仅表现出微弱的抗糖皮质激素活性。在雄性大鼠中，阿索普瑞尼表现出微弱的雄激素和抗雄激素特性。在雌性食蟹猴的毒理学研究中，阿索普瑞尼治疗消除了月经周期和子宫内膜萎缩。阿索普瑞尼在正常志愿者中的早期临床研究表明，无论对排卵的影响如何，月经均呈剂量依赖性抑制，基础雌激素浓度无变化，且无抗糖皮质激素作用。与孕激素不同，阿索普瑞尼不会引起突破性出血。鉴于目前良好的安全性和耐受性，阿索普瑞尼作为子宫肌瘤和子宫内膜异位症等妇科疾病的新型治疗药物似乎很有前景。
