Restricting Placental Transfer of Angiotensin Receptor Blockers to Mitigate Fetal Toxicity: A Potential Therapeutic Strategy for Preeclampsia

Background Enhanced AT 1 R (angiotensin II type 1 receptor) signaling contributes to preeclampsia development; however, angiotensin receptor blockers are contraindicated during pregnancy because of associated fetal toxicity. We aimed to determine whether chemical modification of an angiotensin receptor blocker restricts placental transfer while preserving maternal pharmacological activity. Methods Polyethylene glycol‐modified olmesartan derivatives were synthesized to increase molecular size and hydrophilicity and evaluated in vitro for AT 1 R inhibitory activity. Placental transfer was assessed using an angiotensin II‐induced pregnant mouse model and an ex vivo human placental perfusion model to identify a derivative with reduced placental permeability. The selected compound was evaluated in vivo for pharmacological activity and fetal toxicity in pregnant mice. Results A series of polyethylene glycol‐modified olmesartan derivatives maintained pharmacologically relevant AT 1 R inhibitory activity in vitro. Evaluation in angiotensin II‐treated pregnant mice revealed compound #6, a polyethylene glycol‐modified dimer containing an ionizable tertiary amine, which exhibited reduced placental transfer (∼7% relative to olmesartan). Consistently, compound #6 exhibited minimal transplacental transfer in the human placental perfusion model, comparable to insulin, a negative control. Regarding fetal toxicity, olmesartan induced neonatal renal developmental toxicity at doses as low as one tenth of its minimum effective dose, whereas compound #6 exhibited clear renal toxicity only above its effective dose, indicating a discernible safety margin. Conclusions Restricting placental transfer through rational chemical modification enables decoupling of maternal efficacy from fetal toxicity of angiotensin receptor blockers. Although further optimization is required, these findings provide proof of concept that AT 1 R inhibition may represent a therapeutic strategy for preeclampsia during pregnancy.