1-Alkyl-benzotriazole-5-carboxylic Acids Are Highly Selective Agonists of the Human Orphan G-Protein-Coupled Receptor GPR109b

1-Substituted benzotriazole carboxylic acids have been identified as the first reported examples of selective small-molecule agonists of the human orphan G-protein-coupled receptor GPR109b (HM74), a low-affinity receptor for the HDL-raising drug niacin. No activity was observed at the highly homolog...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-02, Vol.49 (4), p.1227-1230
Main Authors: Semple, Graeme, Skinner, Philip J, Cherrier, Martin C, Webb, Peter J, Sage, Carleton R, Tamura, Susan Y, Chen, Ruoping, Richman, Jeremy G, Connolly, Daniel T
Format: Article
Language:English
Subjects:
Adipocytes - drug effects
Adipocytes - metabolism
Binding Sites
Biological and medical sciences
Carboxylic Acids - chemical synthesis
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Cyclic AMP - biosynthesis
General and cellular metabolism. Vitamins
Humans
Hypolipidemic Agents - chemical synthesis
Hypolipidemic Agents - chemistry
Hypolipidemic Agents - pharmacology
Ligands
Lipolysis - drug effects
Medical sciences
Niacin - pharmacology
Pharmacology. Drug treatments
Receptors, G-Protein-Coupled - agonists
Receptors, Nicotinic
Structure-Activity Relationship
Triazoles - chemical synthesis
Triazoles - chemistry
Triazoles - pharmacology
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Summary:1-Substituted benzotriazole carboxylic acids have been identified as the first reported examples of selective small-molecule agonists of the human orphan G-protein-coupled receptor GPR109b (HM74), a low-affinity receptor for the HDL-raising drug niacin. No activity was observed at the highly homologous high-affinity niacin receptor GPR109a (HM74A). The high degree of selectivity was attributed to a difference in the amino acid sequence adjacent to a key arginineāˆ’ligand interaction allowing somewhat larger ligands to be tolerated by GPR109b.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm051099t