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.
Investigation of the free fatty acid receptor 2 and its role in the treatment of type 2 diabetes mellitus
