Restricting Placental Transfer of Angiotensin Receptor Blockers to Mitigate Fetal Toxicity: A Potential Therapeutic Strategy for Preeclampsia
- 1The University of Tokyo
- 2International University of Health and Welfare
- 3Osaka Metropolitan University
Abstract
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.
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BibTeX
@article{inaoka2026restricting,
title = {{Restricting Placental Transfer of Angiotensin Receptor Blockers to Mitigate Fetal Toxicity: A Potential Therapeutic Strategy for Preeclampsia}},
author = {Naoko Inaoka and Takayuki Iriyama and Yu Ariyoshi and Yuri Yoshida and Seisuke Sayama and Eriko Yano and Haruka Matsui and Kensuke Suzuki and Mari Ichinose and Kenbun Sone and Keiichi Kumasawa and Osamu Wada‐Hiraike and Takeshi Nagamatsu and Tamiko Fumimoto and Takeshi Izawa and Jyoji Yamate and Eri Watanabe and Tomoyuki Nishikawa and Mayumi Ishii and Kayoko Kanamitsu and Toru Iijima and Naoki Suto and Kosuke Yasuda and Yasushi Hirota},
journal = {Journal of the American Heart Association},
year = {2026},
month = oct,
doi = {10.1161/jaha.126.050607},
url = {https://www.ahajournals.org/doi/10.1161/JAHA.126.050607},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Restricting Placental Transfer of Angiotensin Receptor Blockers to Mitigate Fetal Toxicity: A Potential Therapeutic Strategy for Preeclampsia
AU - Naoko Inaoka
AU - Takayuki Iriyama
AU - Yu Ariyoshi
AU - Yuri Yoshida
AU - Seisuke Sayama
AU - Eriko Yano
AU - Haruka Matsui
AU - Kensuke Suzuki
AU - Mari Ichinose
AU - Kenbun Sone
AU - Keiichi Kumasawa
AU - Osamu Wada‐Hiraike
AU - Takeshi Nagamatsu
AU - Tamiko Fumimoto
AU - Takeshi Izawa
AU - Jyoji Yamate
AU - Eri Watanabe
AU - Tomoyuki Nishikawa
AU - Mayumi Ishii
AU - Kayoko Kanamitsu
AU - Toru Iijima
AU - Naoki Suto
AU - Kosuke Yasuda
AU - Yasushi Hirota
PY - 2026
DA - 2026/10/20
JO - Journal of the American Heart Association
DO - 10.1161/jaha.126.050607
UR - https://www.ahajournals.org/doi/10.1161/JAHA.126.050607
AB - 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.
SN - 2047-9980
ER -