Discovery of a novel niacin-lipoic acid dimer N2L attenuating atherosclerosis and dyslipidemia with non-flushing effects.

Niacin has been widely used as an antihyperlipidemic drug, but the flushing effect restricted its clinical application. Here, we developed novel niacin-lipoic acid dimers which lead to better lipid modulation, higher synergistic effects and less side effects. We utilized molecular docking simulation to design a novel series of niacin-lipoic acid dimers. The compound N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)nicotinamide (N2L) was selected for the in vitro and in vivo evaluation, including the agonist activity in CHO-hGPR109A cells, cell protective effects in HT22 and HUVECs cells, flushing effect in guinea pigs and rats, lipid modulation in C57BL/6 mice and high fat diet-rats and atherosclerotic lesions regulation in apolipoprotein E null mice. N2L worked as potent and selective agonists for the high affinity niacin receptor GPR109A. N2L retained antioxidation and cytoprotection of lipoic acid. In addition, N2L displayed a good therapeutic index regarding lipid modulation and atherosclerotic lesions regulation, and minimized niacin-induced vasodilation (flushing) effect in vivo. N2L showed effective treatment regarding to lipid regulation and atherosclerosis inhibition effects, also with excellent antioxidant effects, safety profiles and non-flushing. All these results suggest N2L promising application prospects in the drug development for the treatment of atherosclerosis.