Journal of medicinal chemistry · 2025
Optimization of 2,8-Diaryl-1,5-naphthyridines as Plasmodium falciparum Phosphatidylinositol 4-Kinase Inhibitors with Improved ADME Profiles and In Vivo Efficacy.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Dziwornu Godwin A, Seanego Donald, Fienberg Stephen, Sypu Venkata S, Salomane Nicolaas, Krugmann Liezl, Taylor Dale, Masike Keabetswe, Njoroge Mathew, Boonyalai Nonlawat, Lee Marcus C S, Godoy Luiz C, Pasaje Charisse Flerida, Niles Jacquin C, Basarab Gregory S, Coulson Lauren B, Ghorpade Sandeep R, Chibale Kelly
Аннотация
Previously reported antimalarial Plasmodium phosphatidylinositol 4-kinase IIIβ 2,8-diaryl-1,5-naphthyridine inhibitors have shown suboptimal physicochemical and pharmacokinetic properties. A focused target-based structure-activity relationship and structure-property optimization studies identified several compounds with good target and whole-cell activities and improved physicochemical properties. A new frontrunner compound 27 showed an improved pharmacokinetic profile and reduced parasitaemia (91% at 4 × 50 mg/kg QD doses) in the humanized NOD-scid IL-2Rγnull mouse model of Plasmodium falciparum malaria. Compound 27 poses no hERG channel inhibition at high concentrations or mammalian cytotoxicity but shows low selectivity against related human lipid kinases (PI3Kα and PI4Kβ); however, significantly higher selectivity margins were observed against the human MINK1 and MAP4K4 kinases.