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

摘要

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 see 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 displayed long lasting NEFA and triglyceride lowering effects in healthy male subjects, which were nor associated with flushing. GSK256073 can be used as a pharmacological tool to better understand the role of HCA2 in lipid metabolism. (C) 2015 Elsevier B.V. All rights reserved.