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.

Figure 1

Known GPR120 ligands: part I.

Figure 2

GPR120 pharmacology.

Figure 3

GPR120 spatial distribution and physiological functions in the human body.

Figure 4

Known GPR120 ligands: part II.

Figure 5

From GPR40 to GPR120 agonists: a structural refinement (in green the shifted position of aromatic portion while in blue the heteroatom change, useful to obtain GPR120 selectivity).

Figure 6

Carboxylic acid-head GPR120 agonists.

Figure 7

Nonacidic headgroup GPR120 representative agonists.

Figure 8

Patented general chemical structure useful GPR120 agonists.

Figure 9

SAR opportunities for GPR120 ligands.