Discovery and characterization of GSK256073, a non-flushing hydroxy-carboxylic acid receptor 2 (HCA2) agonist

European Journal of Pharmacology
Dennis SprecherAnne-Charlotte de Gouville

Abstract

Niacin has been used for many years in the treatment of dyslipidemia due to its ability to decrease serum levels of triglycerides and low-density lipoprotein cholesterol and to increase levels of high density lipoprotein cholesterol. However, niacin causes severe flushing resulting in poor patient compliance. The discovery of hydroxy-carboxylic acid receptor 2 (HCA2) as a high affinity receptor for niacin has opened avenues to investigate the mechanism of action of niacin, and to potentially discover agonists which maintain the antilipolytic effects of niacin accessed by a decrease in circulating non-esterified fatty acids (NEFA) and thereby perhaps the lipid/lipoprotein effects, but avoid the flushing effects. Here we describe the strategy we implemented to identify such compounds. This approach resulted in the discovery of GSK256073, a highly potent HCA2 agonist, which produced similar NEFA lowering effects to niacin in preclinical models (rat and guinea pig). A guinea pig model was used to predict flushing, via an increase in ear temperature, and GSK256073 was found to have a minimal effect in this model. These preclinical models appeared to be predictive of human response, since in a first-time-in-human study, GSK256073 dis...Continue Reading

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Citations

Mar 5, 2016·Current Atherosclerosis Reports·Harsh Goel, Richard L Dunbar
Nov 7, 2015·Biochimie·Pauline MorignyDominique Langin
Jan 15, 2017·Trends in Endocrinology and Metabolism : TEM·Stefan Offermanns
Mar 9, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sandeep Kumar Mishra, N Suryaprakash
Dec 14, 2017·Pharmacological Reviews·Darren M RiddyChristopher J Langmead

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