التفاصيل البيبلوغرافية
| العنوان: |
Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials. |
| المؤلفون: |
Delaunois, Annie, Cardenas, Alvaro, Haro, Teresa de, Gerets, Helga H J, Gryshkova, Vitalina, Hebeisen, Simon, Korlowski, Chloé, Laleu, Benoit, Lowe, Martin A, Valentin, Jean-Pierre |
| المصدر: |
Toxicological Sciences; Oct2024, Vol. 201 Issue 2, p321-330, 10p |
| مصطلحات موضوعية: |
SODIUM channels, GUINEA pigs, CARDIOTOXICITY, MALARIA, LEAD compounds |
| مستخلص: |
Quinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture, we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.5-mediated currents in standard patch clamp assays. To understand the mechanism(s) underlying QRS widening to identify further compounds devoid of such liability, we established a set of in vitro models including CaV1.2, NaV1.5 rate-dependence, and NaV1.8 patch clamp assays, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and Langendorff-perfused isolated GP hearts. Six compounds were tested in all models including anesthetized GP, and 8 additional compounds were tested in vitro only. All compounds tested in anesthetized GP and isolated hearts showed a similar cardiovascular profile, consisting of QRS widening, bradycardia, negative inotropy, hypotension, and for some, QT prolongation. However, a left shift of the concentration–response curves was noted from in vitro to in vivo GP data. When comparing in vitro models, there was a good consistency between decrease in sodium spike amplitude in hiPSC-CM and QRS widening in isolated hearts. Patch clamp assay results showed that the QRS widening observed with PMX inhibitors is likely multifactorial, primarily due to NaV1.8 and NaV1.5 rate-dependent sodium blockade and/or calcium channel-mediated mechanisms. In conclusion, early de-risking of QRS widening using a set of different in vitro assays allowed to identify novel PMX inhibitors with improved cardiac safety profile. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |