Dual inhibitors of steroid sulfatase and 17beta-hydroxysteroid dehydrogenase Typ 1 as scientific tools and potential drugs for the treatment of endometriosis: Rational design, synthesis and biological evaluation in vitro and in vivo

子宫内膜异位症是一种依赖雌激素的慢性疾病；它会大大降低生活质量，并造成巨大的医疗和经济成本。大约10%的育龄妇女受到影响，而且没有令人满意的治疗方法。甾体生成酶STS和17betaHSD1在子宫内膜异位症病变中过度表达，并通过增加病变组织中的17β -雌二醇（E2）水平发挥关键作用，由于E2的增殖和抗凋亡作用，刺激疾病的进展。因此，用双重抑制剂抑制这两种酶可能是一种新的有前途的治疗方法，它应该优于鸡尾酒药物或多组分药物的治疗。因此，该项目的目的是合理设计，合成和生物学评价这类双重抑制剂。合成的化合物将在体外进行活性、选择性、代谢稳定性、对肝脏CYPs的抑制、细胞渗透性和毒性的评估。选定的具有合适性质和符合条件的药代动力学抑制剂将用于子宫内膜异位症的啮齿动物模型，分析其对病变发展的影响以及对血浆和选定组织中e2水平的影响。此外，它们对子宫内膜异位症病变和其他组织中e2调控基因表达的影响将通过qPCR进行评估。表达模式的变化将是一个强有力的迹象，表明这些化合物通过干扰e2诱导的信号级联来发挥其作用。具有合适的药效学和药代动力学性质的化合物是阐明子宫内膜e2调节的科学工具和治疗子宫内膜异位症的潜在药物。

Endometriosis is an estrogen-dependent, chronic disease; it can greatly reduce the quality of life and causes substantial medical and economic costs. Approximately 10 % of the women of reproductive age are affected, and no satisfactory treatment is available. The steroidogenic enzymes STS and 17betaHSD1 are over-expressed in endometriotic lesions and play key roles by increasing 17beta-estradiol (E2)-levels in the diseased tissue which, due to the proliferative and anti-apoptotic effects of E2, stimulate the progression of the disease. Therefore, inhibition of both enzymes by dual inhibitors could be a novel and promising therapy approach which should be superior to a treatment with a drug cocktail or a multicomponent drug. Thus, aims of the project are rational design, synthesis and biological evaluation of such dual inhibitors. The synthesized compounds will be assessed in vitro for activity, selectivity, metabolic stability, inhibition of hepatic CYPs, cell permeability and toxicity. Selected inhibitors showing suitable properties and eligible pharmacokinetics will be used in a rodent model for endometriosis where their impact on lesion development as well as their effects on E2-levels in plasma and selected tissues will be analysed. Moreover, their influence on the expression of E2-regulated genes in endometriotic lesions and other tissues will be evaluated using qPCR. Changes in the expression patterns would be a strong indication that the compounds unfold their effects by interfering with E2-induced signaling cascades. Compounds with suitable pharmacodynamic and pharmacokinetic properties are scientific tools for the elucidation of intracrine E2-regulation and potential drugs for the treatment of endometriosis.