Abstract：
Endometriosis is a gynecological disorder affecting about 10% of women and can lead to invalidating painful symptoms and infertility. Since there is no current definitive cure for this disease, new therapeutic options are necessary. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the production of estradiol (E2), the most potent estrogen in women, and of 5-androstene-3β,17β-diol (5-diol), a weaker estrogen than E2, but whose importance increases after menopause. 17β-HSD1 is therefore a pharmacological target of choice for the treatment of estrogen-dependent diseases such as endometriosis. We developed a targeted-covalent (irreversible) and non-estrogenic inhibitor of 17β-HSD1, a molecule named PBRM, and herein evaluated its efficiency for the treatment of endometriosis. In a cell-free assay containing estrone (E1), the natural substrate of 17β-HSD1, PBRM was able to block the formation of E2 in a collection of 50 human endometriosis lesions from a different clinical feature type, location, and phase. When given orally by gavage at 15 mg/kg to baboons, the resulting plasmatic concentration of PBRM was found to be sufficiently high (up to 125 ng/mL) for an efficacy study in a non-human primate (baboon) endometriosis model. After 2 months of treatment, the number of lesions/adhesions decreased in 60% of animals (3/5) in the PBRM-treated group, compared to the placebo group which showed an increase in the number of lesion/adhesions in 60% (3/5) of animals. Indeed, the total number of lesions/adhesions decreased in treated group (-6.5 or -19% when excluding one animal) while it increased in the control group receiving a placebo (+11%). Analysis of specific endometriotic lesions revealed that PBRM decreased the number of red lesions (-67%; 8/12) and white lesions (-35%; 11/31), but not of blue-black lesions. Similarly, PBRM decreased the surface area of dense adhesions and filmy adhesions, as compared to placebo. Also, PBRM treatment did not significantly affect the number of menstrual days. Finally, this targeted covalent inhibitor showed no adverse effects and no apparent toxicity for the duration of the treatment. These data indicate that 17β-HSD1 inhibitor PBRM is a promising candidate for therapy targeting endometriosis and supports the need of additional efforts toward clinical trials.
摘要：
子宫内膜异位症是一种影响约10％妇女的妇科疾病，可导致无效的疼痛症状和不孕症。由于目前尚无这种疾病的最终治愈方法，新的治疗选择是必要的。17β-羟基类固醇脱氢酶1型（17β-HSD1）参与雌二醇（E2）的生产，女性体内最有效的雌激素，和5-雄性激素-3β，17β-二醇（5-二醇），雌激素比E2弱，但其重要性在绝经后增加。因此,17β-HSD1是用于治疗雌激素依赖性疾病如子宫内膜异位症的药理学选择靶标。我们开发了17β-HSD1的靶向共价（不可逆）和非雌激素抑制剂，一种名为PBRM的分子，并在此评估其治疗子宫内膜异位症的效率。在含有雌酮（E1）的无细胞测定中，17β-HSD1的天然底物，PBRM能够阻断来自不同临床特征类型的50个人类子宫内膜异位症病变中E2的形成，location,和阶段。当通过管饲法以15mg/kg口服给予狒狒时，在非人灵长类动物(狒狒)子宫内膜异位症模型的疗效研究中,发现所得PBRM的血浆浓度足够高(高达125ng/mL).治疗2个月后,PBRM治疗组中60%的动物（3/5）的病变/粘连数量减少，与安慰剂组相比，安慰剂组显示60％（3/5）动物的病变/粘连数量增加。的确,治疗组的病变/粘连总数减少(-6.5或-19%,当排除一只动物时),而接受安慰剂的对照组增加(+11%).对特定子宫内膜异位病变的分析显示，PBRM减少了红色病变（-67％；8/12）和白色病变（-35％；11/31）的数量，但不是蓝黑色的病变.同样，PBRM减少了致密粘连和膜粘连的表面积，与安慰剂相比。此外，PBRM治疗对月经天数没有显著影响。最后,该靶向共价抑制剂在治疗期间未显示不良反应和明显毒性.这些数据表明17β-HSD1抑制剂PBRM是靶向子宫内膜异位症的疗法的有希望的候选者,并且支持需要针对临床试验的额外努力。
