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GPBAR1(also known as TGR5) is a G-protein-coupled receptor (GPCR)that triggers intracellular signals upon ligation by various bileacids. The receptor has been studied mainly for its function in energyexpenditure and glucose homeostasis, and there is little informationon the role of GPBAR1 in the context of inflammation. After a high-throughputscreening campaign, we identified isonicotinamides exemplified bycompound 3as nonsteroidal GPBAR1 agonists. We optimizedthis series to potent derivatives that are active on both human andmurine GPBAR1. These agonists inhibited the secretion of the proinflammatorycytokines TNF-α and IL-12 but not the antiinflammatory IL-10in primary human monocytes. These effects translate in vivo, as compound 15inhibits LPS induced TNF-α andIL-12 release in mice. The response was GPBAR1 dependent, as demonstratedusing knockout mice. Furthermore, agonism of GPBAR1 stabilized thephenotype of the alternative, noninflammatory, M2-like type cellsduring differentiation of monocytes into macrophages. Overall, ourresults illustrate an important regulatory role for GPBAR1 agonistsas controllers of inflammation. [ABSTRACT FROM AUTHOR]