Nitrogen-Containing Heterocycles as Novel GPR109A Agonists for the Treatment of Dyslipidemia

Objective: The current study focuses on the design and synthesis of novel nitrogen-containing heterocycles for the treatment of hyperlipidemia. The development of new N-containing heterocycles as GPR109A agonists, similar to niacin but without its drawbacks, is highly desirable. Methods: Molecular modeling studies were performed using a new 3D crystal structure of the GPR109A receptor, which was prepared by homology modeling. The nitrogen-containing heterocycles were synthesized via a one-pot method and characterized by IR, 1H NMR, and mass spectrometry. The compounds were evaluated in acute triton-induced and cafeteria diet-induced chronic hyperlipidemia models in rats. A 3D structure of GPR109A was generated by homology modeling and deposited in the Protein Model Database (PMDB) under the identifier PM0083972. Results and Discussion: In docking analyses of 80 compounds, 78 exhibited binding energies lower than that of nicotinic acid; only two compounds showed binding energies higher than nicotinic acid. Compound 2b, (R)-methyl 2-(2-(1H-indol-3-yl)acetamido)-3-(1H-indol-3-yl)propanoate, demonstrated the highest binding affinity (–30.54 kcal/mol) compared to the standard, nicotinic acid (–17.68 kcal/mol). In both the acute triton and cafeteria diet-induced chronic models, compound 2b produced a significant reduction in lipid levels and an elevation of HDL levels compared to nicotinic acid. Histopathological examination of liver tissue from rats treated with compound 2b revealed normal centrilobular hepatocytes, indicating reduced hepatotoxicity. Based on in silico and in vivo studies, compound 2b exhibited lower liver toxicity, which may be attributed to the replacement of the pyridine ring in nicotinic acid with a nitrogen-containing indole heterocycle. Conclusions: Compound 2b represents a promising pharmacophore for further structural modification to develop more potent molecules for the treatment of hyperlipidemia.