GPR120/FFAR4 Pharmacology: Focus on Agonists in Type 2 Diabetes Mellitus Drug Discovery

Abstract

The G-protein coupled receptors (GPCRs) activated by free fatty acids (FFAs) have emerged as new and exciting drug targets, due to their plausible translation from pharmacology to medicines. This perspective aims to report recent research about GPR120/FFAR4 and its involvement in several diseases, including cancer, inflammatory conditions, and central nervous system disorders. The focus is to highlight the importance of GPR120 in Type 2 diabetes mellitus (T2DM). GPR120 agonists, useful in T2DM drug discovery, have been widely explored from a structure–activity relationship point of view. Since the identification of the first reported synthetic agonist TUG-891, the research has paved the way for the development of TUG-based molecules as well as new and different chemical entities. These molecules might represent the starting point for the future discovery of GPR120 agonists as antidiabetic drugs.

Free Fatty Acid Receptors (FFARs) In Adipose: Physiological Role and Therapeutic Outlook

“…TAK-875 had shown promising efficacy and significantly reducing HbA1C levels without causing any hypoglycemic episodes. However, during phase 2 clinical trials the compound was found to cause liver toxicity and further development of the drug was discontinued [60,61]. Efforts are on to develop safer alternatives with good efficacy and with no or little toxicity [16,20,62].…”

“…TUG-891 was also able to induced phosphorylation of FFAR4 followed by receptor internalization. TUG-891 was able to mimic almost all the beneficial properties of natural agonists of FFAR4 including GLP-1 secretion from enteroendocrine cells, augmenting glucose uptake in murine adipocytes and inhibiting inflammatory mediators from macrophages [60,66,69]. TUG-891 was also shown to reduce food intake, enhance insulin signaling and reverse insulin resistance in mice.…”

Free Fatty Acid Receptors (FFARs) in Adipose: Physiological Role and Therapeutic Outlook

“…Ever since the members of the FFAR family were de-orphanized, their role in different biological processes has been extensively studied. In particular, their contribution to metabolic and energy homeostasis has been comprehensively recognized, and they have attracted considerable attention in the drug discovery field [ 56 , 57 , 58 , 59 ]. As a result, several ligands of FFARs have been developed to use as therapeutic drugs for metabolic diseases like diabetes and obesity.…”

Thiazolidinedione derivatives as novel GPR120 agonists for the treatment of type 2 diabetes

“…1 ). 17 Polar groups are generally carboxylic acids, which play an important role in agonistic activity. TUG-891, the first potent and selective GPR120 agonist, developed at the University of Southern Denmark has been widely used to explore the physiological function of GPR120.…”