GPR120 agonists for the treatment of diabetes: a patent review (2014 present)

Introduction: G protein-coupled receptor 120 (GPR120) is a G_αq coupled GPCR specifically activated by long-chain fatty acids (LCFAs). Functionally, it has been identified as a member of a family of lipid-binding free fatty acid receptors including GPR40, GPR41, and GPR43. Upon stimulation by LCFAs, GPR120 can directly or indirectly modulate hormone secretion from the gastrointestinal tract and pancreas, and regulate lipid and/or glucose metabolism in adipose, liver, and muscle tissues. Additionally, GPR120 is postulated to mediate anti-inflammatory and insulin-sensitizing effects in adipose and macrophages. These benefits suggest that GPR120 agonists have the potential to be an effective treatment for obesity, type 2 diabetes mellitus (T2DM), and other metabolic syndromes.

Area covered: This article highlights and reviews research advances in this field that have been published in patent literature and peer-reviewed journals since 2014.

Expert opinion: Current development has been hindered by species differences in GPR120 distribution, differences in GPR120-mediated signaling in distinct tissue types, and lack of available ligands with suitable selectivity for GPR120 over GPR40 in both human and rodents. The discovery of β-arrestin biased GPR120 agonists will help elucidate the potential of selective therapeutics that may discriminate between desirable and undesirable pharmacological effects.

Abbreviations: ALA: α-linolenic acid; AUC: area under the curve; BRET: bioluminescence resonance energy transfer; CCK: cholecystokinin; CHO-K1 cell: Chinese hamster ovary-K1 cell; db/db mouse: diabetic mouse; DHA: docosahexaenoic acid; DIO: diet-induced obesity; DMSO: dimethyl sulfoxide; DPP-4: dipeptidyl peptidase 4; EPA: eicosapentaenoic acid; FA(s): fatty acid(s); FFA(s): free fatty acid(s); FFAR: free fatty acid receptor; FLIPR: fluorescent imaging plate reader; GIR: glucose infusion rate; GLP-1: glucagon-like peptide 1; GP(C)R: G protein-coupled receptor; GSIS: glucose-stimulated insulin secretion; HEK293 cell: human embryonic kidney 293 cell; HOMA-IR: homeostatic measurement assessment of insulin resistance; IP1: inositol phosphate turnover; IPGTT: intraperitoneal glucose tolerance test; LCFA(s): long-chain fatty acid(s); MED_max: maximal efficacy; MIN6 cell: mouse insulin-secreting cell; NPY: neuropeptide Y; OGTT: oral glucose tolerance test; pERK: phosphorylated ERK; PPAR: peroxisome proliferator-activated receptor; QD: once daily; SAR: structure-activity relationship; siRNA: small interfering ribonucleic acid; STC-1: intestinal secretin tumor cell; T2DM: type 2 diabetes mellitus; U2OS cell: human bone osteosarcoma epithelial cell; uHTS: ultrahigh-throughput screening; ZDF: zucker diabetic fatty.

Keywords: G-protein-coupled receptors; GPR120; fatty acid; inflammation; insulin sensitizer; metabolic syndrome; obesity; type 2 diabetes mellitus.