A key feature of type 2 diabetes is insulin resistance, a large component of which is obesity driven. The accumulation of macrophages and pro-inflammatory cytokines, especially in fat tissue and the liver, leads to chronic inflammation which is believed to be a primary driver of this component. Many studies have identified long-chain w-3-fatty acids as beneficial dietary nutrients which, among other things, produce anti-inflammatory outcomes. Macrophages express high levels of a key receptor for these molecules, GPR120, and their interaction with it has been reported to improve insulin sensitivity despite relatively low affinity for the receptor. A dihydrobenzofuran scaffold represented one of our key starting points for the identification of potent and selective GPR120 agonists. The evolution of this pharmacophore from an SAR standpoint as well as the mitigation of its off-target PXR induction activity will be discussed.

Discovery and SAR of benzofuran GPR120 agonists

250th National Meeting (2015)

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