Background: Nicotinic acid (NA) has been used as a drug to treat dyslipidemia for > 50 years. In outcome clinical trials, NA displayed remarkable efficacy in patients with cardiovascular diseases by modifying lipid profiles that results in reduced morbidity and mortality. On the other hand, NA induces vasodilation (flushing) that undermines treatment compliance. In addition, high-dose treatment is required presumably owing to the poor pharmacokinetic properties of NA. The identification of the high-affinity NA receptor, namely G-protein coupled receptor 109A (GPR109A), led to further understanding of the pharmacological effects of NA and discovery of compounds that are potentially superior in efficacy yet devoid of NA's adverse effects.
Objective/method: This review focuses on the endeavors of several pharmaceutical companies to discover and develop GPR109A agonists. Representative compounds of each series in patent literature since 2005 are highlighted.
Conclusion: Highly potent GPR109A agonists with minimal flushing effects and robust free fatty acid reduction have been identified. Despite the failure of the partial agonist MK-0354 to achieve efficacy in a Phase II clinical trial, at least three other GPR109A agonists have been evaluated in clinical trials. The upcoming clinical data would be critical to validate the therapeutic utility of this receptor.