Curr Top Med Chem. 2026 Jul 26. doi: 10.2174/0115680266466273260722130035. Online ahead of print.
ABSTRACT
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate metabolic homeostasis and represent important therapeutic targets for conditions such as type 2 diabetes, dyslipidemia, and cardiovascular disease. While classical modulators often rely on carboxylic acid moieties to anchor receptor binding through hydrogen bonding, such groups are associated with suboptimal pharmacokinetic profiles, including poor bioavailability, rapid metabolism, and limited tissue penetration. This review explores the strategic use of bioisosteres, such as thiazolidinediones, tetrazoles, oxadiazolones, sulfonamides, and acetamides, as alternative polar headgroups in the design of PPAR ligands. We provide an overview of several aspects, highlighting how structural modifications to polar headgroups influence binding modes, receptor selectivity, and agonist profiles in the development of safer and more effective PPAR modulators. Emphasis is placed on synthetic approaches that prioritize convergent, high-yield, and late-stage diversification to facilitate parallel structure-activity relationship (SAR) exploration. Together, these bioisosteric strategies highlight the synergy between medicinal chemistry and synthetic innovation in the pursuit of next-generation PPAR modulators. Future efforts aimed at partial, biased, or tissue-selective agonists will benefit from continued exploration of novel headgroups, enabling safer and more effective therapies for metabolic and inflammatory diseases. Overall, a comparison of the different bioisosteric classes underscores the pivotal role of polar headgroup design in tuning potency, selectivity, and safety, guiding the rational development of future PPAR-targeted therapeutics.
PMID:42522647 | DOI:10.2174/0115680266466273260722130035