Background: The global incidence of type 2 diabetes mellitus (T2DM) has enthused the
development of new antidiabetic targets with low toxicity and long-term stability. In this respect, free
fatty acid receptor 1 (FFAR1), which is also recognized as a G protein-coupled receptor 40 (GPR40),
is a novel target for the treatment of T2DM. FFAR1/GPR40 has a high level of expression in β-cells
of the pancreas, and the requirement of glucose for stimulating insulin release results in immense
stimulation to utilise this target in the medication of T2DM.
Methods: The data used for this review is based on the search of several scienctific databases as well
as various patent databases. The main 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, its role in T2DM, recent developments
in small molecule FFAR1 (GPR40) agonists reported till now, compounds of natural/plant
origin, recent patents published in the 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
demonstrated their probable role in the improvement of glucose control. Though, there are some
problems still to be resolved in this field as some FFAR1 agonists terminated in the late phase of
clinical studies due to “hepatotoxicity.” Currently, PBI-4050 is under clinical investigation by
Prometic. Further investigation of pharmacophore scaffolds for FFAR1 full agonists as well as multitargeted
modulators and corresponding clinical investigations will be anticipated, which can open up
new directions in this area.