Background: Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors activated
by endogenous fatty acids and prostaglandins that are classified into three types: α, γ and δ,
which have different functions and tissue distribution. PPAR modulators have been exploited to the
treatment of important metabolic diseases, such as type 2 diabetes mellitus and metabolic syndrome,
which are considered relevant epidemic diseases currently. Along the last decades, several studies
have reported structural differences between the three PPAR subtypes associated with the discovery of
selective ligands, dual and pan-agonists. Nowadays, there are several approved drugs that activate
PPARα (fibrates) and PPARγ (glitazones), but up to now there is none clinically used drug targeting
PPARδ. Additionally, several side-effects associated with the use of PPARα and γ agonists are reported
by regulatory agencies, which do not indicate anymore their use as first-line drugs.
Objective: A significant new market has grown in the last years, focusing on the development of new
PPARδ agonists as drug candidates to treat metabolic diseases and, in this sense, this study proposes
to review the structural requirements to achieve selective PPARδ activation, as well to discuss the
most relevant agonists in clinical trials, providing information on the current phase in the drug discovery
and design targeting PPARδ.
Conclusion: Several PPARδ ligands with high potency were reported in the literature and were designed
or discovered by a combination of experimental and computational approaches. Furthermore, the reported
importance of pockets and individual residues at PPARδ binding site as well as the importance of substituent
and some physicochemical properties that could help to design of new classes of agonists.