Advances and Challenges in Drug Design of PPARd Ligands

Background: Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors activated by endogenous fatty acids and prostaglandins that are classified into three types: a, g and d, 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 PPARa (fibrates) and PPARg (glitazones), but up to now there is none clinically used drug targeting PPARd. Additionally, several side-effects associated with the use of PPARa and g 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 PPARd agonists as drug candidates to treat metabolic diseases and, in this sense, this study proposes to review the structural requirements to achieve selective PPARd 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 PPARd. Conclusion: Several PPARd 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 PPARd binding site as well as the importance of substituent and some physicochemical properties that could help to design of new classes of agonists.