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

• Applicants: Dr. Martin Frotscher; Professor Matthias W. Laschke, Ph.D.
• Subject Area: Pharmacy
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 281740749

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.

• DFG Programme: Research Grants