Pre-clinical studies to repurpose FDA-approved drugs for tocolytic use

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PROJECT SUMMARY Preterm birth (PTB) rates continue to increase, with over 15 million PTB/year worldwide, constituting ~10% of live births globally. The common denominator for all known causes of PTB is the early activation of uterine contractions. Current tocolytics used to inhibit uterine contractions are limited by their undesirable off-target effects and short duration of benefit. Thus, an undisputed necessity exists for discovering novel tocolytic agents with improved safety and efficacy. There is almost a complete lack of drug development for preterm labor (PTL) and other obstetric indications. In the traditional drug development process, approximately two-thirds of investigational drugs fail in clinical trials due to unexpected toxicity or lack of efficacy. Thus, the current application is centered on the repurposing of existing FDA-approved drugs for novel therapeutic tocolytic use. We have screened the FDA collection of drugs in a phenotypic uterine myometrial cell contractility assay, and identified drugs that affect a final common calcium (Ca2+)-mobilization pathway involved in the initiation of labor. We have subsequently screened for uterine selectivity by omitting drugs that antagonized Ca2+-mobilization in various vascular smooth muscle cells, which are off-target tissues of current tocolytics. Our preliminary studies identified 20 hit-drugs that are uterine selective in their ability to inhibit oxytocin-induced intracellular Ca2+-signaling, and thus, contractility. Since these hit-drugs are already FDA-approved, the majority of in vitro and in vivo drug metabolism, pharmacokinetics and toxicity studies have been performed, therefore the drugs are ready for pre- clinical studies. The goal of this application is to examine the in vitro and in vivo efficacy of FDA-approved drugs to regulate uterine contractility without adverse maternal and fetal effects. In Aim 1 we will test the ex vivo tocolytic efficacy, as well as placental transfer and metabolism, of lead-drugs using human myometrium and placenta, respectively. In Aim 2 we will determine in vivo effect of lead-drugs on intrauterine contractile pressure, timing of delivery and maternal/fetal health status in mice. Finally in Aim 3, we will identify synergistic drug combinations to regulate in vitro human myometrial contractility. The successful completion of our studies will provide valuable information for further pre-clinical development of tocolytic drugs or phase-I clinical trials for women with PTL.