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Design and synthesis of atorvastatin derivatives with enhanced water solubility, hepatoselectivity and stabilityстатья
- Авторы: Maklakova Svetlana, Lopukhov Anton, Khudyakov Alexandr, Kovalev Sergey V., Mazhuga Maria, Chepikova Olga, Zamyatnin Andrey, Majouga Alexander, Klyachko Natalia L., Beloglazkina Elena K.
- Журнал: RSC Medicinal Chemistry
- Том: 14
- Год издания: 2023
- Издательство: Royal Society of Chemistry
- Местоположение издательства: United Kingdom
- Первая страница: 56
- Последняя страница: 64
- DOI: 10.1039/d2md00119e
- Аннотация: Statins are effective 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) inhibitors, which are successfully used for cardiovascular diseases treatment. Statins’ side effects are generally attributed to poor bioavailability and hepatoselectivity, which are closely related to their high lipophilicity. Targeted delivery of statins to the liver is considered a way to reduce unwanted side effects. Herein we report on synthesis and evaluation of atorvastatin conjugates targeting the galactose-specific hepatic asialoglycoprotein receptor (ASGPR). The prepared conjugates showed greater water solubility compared to unmodified atorvastatin. The synthesised compounds demonstrated potent binding to ASGPR with submicromolar KD values. The conjugates with an amide bond connecting atorvastatin and the targeting moiety displayed the optimal stability under model conditions, as they underwent hydrolysis only when incubated with the intracellular protease. The hydrolysis products effectively inhibited HMG-R activity. The results suggest that the designed amide-based compounds have the potential to be further developed as orally administered prodrugs of atorvastatin.
- Добавил в систему: Маклакова Светлана Юрьевна
Прикрепленные файлы
| № | Имя | Описание | Имя файла | Размер | Добавлен |
|---|---|---|---|---|---|
| 1. | Первая страница | First_page.pdf | 616,7 КБ | 13 октября 2022 [maklakova.svetlana] |