{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:38:20Z","timestamp":1792647500870,"version":"4.5.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Enhanced AT\n                      <jats:sub>1<\/jats:sub>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Polyethylene glycol\u2010modified olmesartan derivatives were synthesized to increase molecular size and hydrophilicity and evaluated in\u00a0vitro for AT\n                      <jats:sub>1<\/jats:sub>\n                      R inhibitory activity. Placental transfer was assessed using an angiotensin II\u2010induced pregnant mouse model and an ex\u00a0vivo human placental perfusion model to identify a derivative with reduced placental permeability. The selected compound was evaluated in\u00a0vivo for pharmacological activity and fetal toxicity in pregnant mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      A series of polyethylene glycol\u2010modified olmesartan derivatives maintained pharmacologically relevant AT\n                      <jats:sub>1<\/jats:sub>\n                      R inhibitory activity in\u00a0vitro. Evaluation in angiotensin II\u2010treated pregnant mice revealed compound #6, a polyethylene glycol\u2010modified dimer containing an ionizable tertiary amine, which exhibited reduced placental transfer (\u223c7% 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      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\n                      <jats:sub>1<\/jats:sub>\n                      R inhibition may represent a therapeutic strategy for preeclampsia during pregnancy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.126.050607","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:52:55Z","timestamp":1791373975000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Restricting Placental Transfer of Angiotensin Receptor Blockers to Mitigate Fetal Toxicity: A Potential Therapeutic Strategy for Preeclampsia"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3150-9948","authenticated-orcid":false,"given":"Naoko","family":"Inaoka","sequence":"first","affiliation":[{"name":"The University of Tokyo","place":["Tokyo, 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