Design and synthesis of atorvastatin derivatives with enhanced water solubility, hepatoselectivity and stability

Statins are effective 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) inhibitors, which are successfully used for cardiovascular disease treatment. Statins' side effects are generally attributed to poor bioavailability and hepatoselectivity, which are closely related to their high lipop...

Full description

Saved in:
Bibliographic Details
Published in:MedChemComm 2023-01, Vol.14 (1), p.56-64
Main Authors: Maklakova, Svetlana Yu, Lopukhov, Anton V, Khudyakov, Alexandr D, Kovalev, Sergey V, Mazhuga, Maria P, Chepikova, Olga E, Zamyatnin, Andrey A, Majouga, Alexander G, Klyachko, Natalia L, Beloglazkina, Elena K
Format: Article
Language:English
Subjects:
Atorvastatin
Bioavailability
Cardiovascular diseases
Chemistry
Coenzyme A
Conjugates
Galactose
Hydrolysis
Hydroxymethylglutaryl-CoA reductase
Medical treatment
Oral administration
Reductases
Side effects
Solubility
Stability
Statins
Synthesis
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Statins are effective 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) inhibitors, which are successfully used for cardiovascular disease 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 as 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 the ASGPR with submicromolar K D 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. Atorvastatin conjugates targeting the galactose-specific hepatic asialoglycoprotein receptor with improved stability are reported.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d2md00119e