Drug repurposing identifies candidate uterus-selective tocolytics for preterm labor.

At present, there are no US Food and Drug Administration (FDA)-approved tocolytics for the management of preterm labor. To identify drugs for repurposing as tocolytics, a phenotypic high-throughput screen against a library of 1191 FDA-approved drugs was performed for inhibitors of in vitro uterine myometrial contractions. A total of 51 drugs inhibited calcium (Ca2+) mobilization in primary human myometrial cells. To minimize potential off-target effects, hit drugs were counterscreened against primary human aortic vascular smooth muscle cells, identifying 10 uterine-selective drugs. Of these, two drugs, the antiemetic fosaprepitant dimeglumine and the glucocorticoid ciclesonide, displayed favorable in vitro therapeutic indices (TIs > 5), inhibited contractions in human myometrial tissue ex vivo, and did not alter tone in the fetal murine ductus arteriosus ex vivo. Next, the potential synergy among hit drugs and clinically used tocolytics was evaluated using a high-throughput combination screen based on Ca2+ mobilization in primary human myometrial cells. Four synergistic drug combinations incorporating ciclesonide, indomethacin, ivermectin, atosiban, or nelfinavir mesylate displayed favorable TIs of >5 and improved ex vivo tocolytic potency, efficacy, or both. Last, aprepitant, ciclesonide, and four synergistic drug combinations delayed delivery until term and improved neonatal viability and skin and lung maturation in a mouse model of induced preterm labor, with several combinations outperforming their component drugs. This approach established a systematic strategy for identifying uterus-selective tocolytics, and these findings support further preclinical development of repurposed drugs and drug combinations for the treatment of preterm labor to improve pregnancy and neonatal outcomes.