Recent Updates on Free Fatty Acid Receptor 1 (GPR-40) Agonists for the Treatment of Type 2 Diabetes Mellitus

Abstract

Background: The disturbing incidence of type 2 diabetes mellitus (T2DM) enthused the development of newer antidiabetic targets with low toxicity and longer stability. In this respect, free fatty acid receptor 1 (FFAR1), also recognized as G protein-coupled receptor 40 (GPR40) is novel target for the treatment of T2DM. FFAR1/GPR40 have high level of expression in β-cells of pancreas and requirement of glucose for stimulating insulin release results in immense stimulation to utilise these targets in the medication of T2DM. Methods: Data used for this review was based on search from several science databases as well as various patent databases. The main data search terms used were free fatty acid receptor 1, FFAR1, FFAR1 agonists, diabetes mellitus, G protein coupled receptor 40 (GPR40), GPR40 agonists, GPR40 ligands, type 2 diabetes mellitus and T2DM. Results: The present review article gives a brief overview of FFAR1, role in T2DM, recent developments in small molecule FFAR1 (GPR40) agonists reported till now, compounds of natural/plant origin, recent patents published in last few years, mechanism of FFAR1 activation by the agonists, and clinical status of the FFAR1/GPR40 agonists. Conclusion: The agonists of FFAR1/GRP40 showed considerable potential for the therapeutic control of T2DM. Most of the small molecule FFAR1/GPR40 agonists developed were aryl alkanoic acid derivatives (such as phenylpropionic acids, phenylacetic acids, phenoxyacetic acids and benzofuran acetic acid derivatives) and thiazolidinediones. Some natural/plant derived compounds including fatty acids, sesquiterpenes, phenolic compounds, anthocyanins, isoquinoline and indole alkaloids were also reported as potent FFAR1 agonists. The clinical investigations of the FFAR1 agonists had demonstrated their probable role in the improvement of glucose control. Though, there are some problems still to be resolved in this field since some FFAR1 agonists terminated in late phase of clinical studies due to “hepatotoxicity”. Currently, PBI-4050 is under clinical investigation by Prometic. Furthermore, the more investigation of pharmacophore scaffolds for FFAR1 full agonists as well as multi-targeted modulators and corresponding clinical investigations will be anticipated which could open up new directions in this area.

Blood–Brain Barrier Disruption Mediated by FFA1 Receptor—Evidence Using Miniscope

“…Lysophosphatidylcholine (LPC), an endogenous ligand for GPR119 receptor, has also been reported to exert some of its metabolic effects by activating FFA1/GPR40 and GPR55 [54][55][56]. Moreover, FFA1-selective agonists are still being considered as potential therapeutic agents for the treatment of metabolic disorders such as type 2 diabetes [57][58][59]. In addition, the transient increase in BBB permeability produced by FFA1 activation can facilitate access to the brain by other drugs which are administered concomitantly with DHA/n-3 PUFAs, or can be used as a potential tool to improve drug delivery to the brain [60,61].…”

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

“…The main objective for the GPR40 agonist designers has been to devise compounds structurally different to FFAs and much more potent than FFAs [ 54 , 55 ]. This was in order to avoid lipotoxicity, which may contribute to diabetes progression [ 56 , 57 ].…”

Efficacy of Huanglian Jiedu Decoction for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

“…Although these interventions have been shown to be effective in controlling blood glucose levels, many oral antidiabetic medications, such as metformin, sulfonylureas, and thiazolidinediones, can lead to undesirable side effects including gastrointestinal distress, weight gain, and increased risk of hypoglycemia, which affect patient compliance and quality of life [4]. Moreover, the prolonged use or high-dose therapy of certain medications has been linked to other health concerns, notably liver and kidney damage [5‒8]. This underscores the pressing need to explore novel therapeutic strategies and interventions.…”