Hepatoprotective Effect of a New FFAR1 Agonist—N-Alkylated Isobornylamine

Abstract

Free fatty acid receptor-1 (FFAR1) is one of the possible therapeutic targets in the search for new hepatoprotective drugs. FFAR1 agonists were found to have hypolipidemic, antifibrotic, anti-inflammatory, antiproliferative and antioxidant effects in addition to hypoglycemic action. In this work, we conducted a study of the hepatoprotective effect of the compound QS-528 (previously discovered as an agonist of FFAR1) at doses of 60, 90, 120 and 150 mg/kg on carbon tetrachloride (CCl4)-induced liver injury. At the end of the experiment, a biochemical blood assay demonstrated that the introduction of QS-528 dose-dependently reduces the levels of liver enzymes (AST, ALT and ALKP). Histological and morphometric studies of animals’ livers treated with QS-528 at doses of 120 and 150 mg/kg showed a decrease in degenerative/necrotic changes in hepatocytes and an increase in the regenerative activity of the liver. In addition, no toxicity at a single oral dose of 1000 mg/kg and an increase in HepG2 cell viability in vitro were found. Thus, the compound QS-528 was found to exhibit a hepatoprotective effect against CCl4-induced toxic liver damage.

Bornyl-Containing Derivatives of Benzyloxyphenylpropanoic Acid as FFAR1 Agonists: In Vitro and In Vivo Studies

“…Like the compound SCO-267, QS-528 also resolved fatty liver dystrophy in mice in our experiment ( Figure 9 d) and reduced TG ( Figure 6 ) and ALT concentrations ( Figure 7 ). The observed hepatoprotective effect was also found earlier in a tetrachlomethane-induced model of liver injury [ 29 ]. It is worth noting that the compound SCO-267 was initially found to have hypoglycemic effects [ 30 ], followed by hepatoprotective effects [ 11 ].…”

“…Consequently, compound QS-619 is safe for long-term use, an extremely important characteristic of a potential drug [32]. The acute toxicity of compound QS-528 was studied previously at a dose of 1000 mg/kg and similar results were obtained [29].…”

Synthesis and Evaluation of Hypoglycemic Activity of Structural Isomers of ((Benzyloxy)phenyl)propanoic Acid Bearing an Aminobornyl Moiety

“…Previously, we synthesized a (hydroxyphenyl)propanoic acid derivative QS-528 containing a terpene fragment, which was shown to have good affinity for the receptor discussed and also to induce a hypoglycemic effect in the oral glucose tolerance test (OGTT) with mice [24]. Further studies of this compound revealed other useful effects, as we propose, reduction of fatty degeneration of the liver and a hepatoprotective effect in mice [25,26]. Based on our results, we consider the structural analogs of QS-528 to be promising compounds for subsequent studies.…”

(1R,2R,4R)-N-((4-((4-(2-Carboxyethyl)phenoxy)methyl)thiophen-2-yl)methyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-aminium Chloride

“…QS-528 has been shown to exhibit an affinity to FFAR1 during in vitro tests in the submicromolar concentration and also had a hypoglycemic effect in an oral glucose tolerance test (OGTT) on mice [9]. Further studies of this compound revealed other useful effects, such as reduction of fatty degeneration of the liver and a hepatoprotective effect in mice [10,11]. Based on our results, we consider the structural analogues of QS-528 to be promising compounds for the therapy of DM2.…”