title: Discovery and characterization of GSK256073, a non-flushing hydroxy-carboxylic acid receptor 2 (HCA2) agonist.
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 displayed long lasting NEFA and triglyceride lowering effects in healthy male subjects, which were not associated with flushing. GSK256073 can be used as a pharmacological tool to better understand the role of HCA2 in lipid metabolism.
authors.affiliation: GlaxoSmithKline Laboratories, Metabolic Pathways and Cardiovascular Unit, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Sprecher
authors.affiliation: GlaxoSmithKline Laboratories, Gunnels Wood Road, Stevenage, Hertfordshire, UK.
authors.forename: Miles
authors.initials: M
authors.lastname: Maxwell
authors.affiliation: GlaxoSmithKline Laboratories, Gunnels Wood Road, Stevenage, Hertfordshire, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Goodman
authors.affiliation: GlaxoSmithKline Laboratories, Gunnels Wood Road, Stevenage, Hertfordshire, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: White
authors.affiliation: GlaxoSmithKline Laboratories, Gunnels Wood Road, Stevenage, Hertfordshire, UK.
authors.forename: Chi-Man
authors.initials: CM
authors.lastname: Tang
authors.affiliation: GlaxoSmithKline Laboratories, Centre de Recherche François Hyafil, 27 av du Quebec, 91951 Les Ulis Cedex, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Boullay
authors.affiliation: GlaxoSmithKline Laboratories, Centre de Recherche François Hyafil, 27 av du Quebec, 91951 Les Ulis Cedex, France. Electronic address: Anne-Charlotte.m.degouville@gsk.com.
authors.forename: Anne-Charlotte
authors.initials: AC
authors.lastname: de Gouville
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005483:Flushing / Q000139:chemically induced*; D006168:Guinea Pigs; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011687:Purines / Q000009:adverse effects* / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D014280:Triglycerides / Q000378:metabolism; D014970:Xanthines / Q000009:adverse effects* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C000604188:8-chloro-3-pentyl-1H-purine-2,6(3H,7H)-dione; D005230:Fatty Acids, Nonesterified; C530636:HCAR2 protein, human; D011687:Purines; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014280:Triglycerides; D014970:Xanthines; D000242:Cyclic AMP
keywords: Dyslipidemia; Flushing; GSK 256073 (PubChem CID 46215799); GSK256073; Hydroxy-carboxylic acid receptor 2 (HCA2); NEFA; Niacin; Niacin (PubChem CID 938)