Role of Chain Length and Degree of Unsaturation of Fatty Acids in the Physicochemical and Pharmacological Behavior of Drug–Fatty Acid Conjugates in Diabetes

• Published in: Journal of medicinal chemistry 2021-10, Vol.64 (19), p.14217-14229
• Main Authors: Singh, Arihant Kumar, Italiya, Kishan S, Narisepalli, Saibhargav, Chitkara, Deepak, Mittal, Anupama
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Diabetes Mellitus, Type 1 - chemically induced; Diabetes Mellitus, Type 1 - drug therapy; Dose-Response Relationship, Drug; Fatty Acids - chemistry; Fatty Acids - pharmacology; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Mice; Molecular Structure; Prodrugs - chemistry; Prodrugs - pharmacology; Rats; Rats, Wistar; Streptozocin; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00391

Several drug–fatty acid (FA) prodrugs have been reported to exhibit desirable physicochemical and pharmacological profile; however, comparative beneficial effects rendered by different FAs have not been explored. In the present study, four different FAs (linoleic acid, oleic acid, palmitic acid, and α-lipoic acid) were selected based on their chain length and degree of unsaturation and conjugated to Lisofylline (LSF), an antidiabetic molecule to obtain different drug–FA prodrugs and characterized for molecular weight, hydrophobicity, purity, self-assembly, and efficacy in vitro and in vivo in type 1 diabetes model. Prodrugs demonstrated a 2- to 6-fold increase in the plasma half-life of LSF. Diabetic animals treated with prodrugs, once daily for 5 weeks, maintained a steady fasting blood glucose level with a significant increase in insulin level, considerable restoration of biochemical parameters, and preserved β-cells integrity. Among the different LSF-FA prodrugs, LSF-OA and LSF-PA demonstrated the most favorable physicochemical, systemic pharmacokinetic, and pharmacodynamic profiles.