Fluorinated pyrazole acids are agonists of the high affinity niacin receptor GPR109a

A series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.

Graphical abstractA series of 4-fluoro-5-functionalized pyrazole-3 carboxylic acids were shown to be potent, selective agonists of GPR109a. Improved free fatty acid reduction was observed when compared to niacin.Figure optionsDownload full-size imageDownload as PowerPoint slide