Trends in Developing PPAR-Gamma and FFAR1/GPCR40 Modulators for Managing Type-II Diabetes Mellitus.

Abstract

Agonists of peroxisome proliferator-activated receptor-gamma (PPAR-γ) gained the main interest for managing type-II diabetes mellitus (T2DM) as insulin sensitizers. Serving as 2nd-line therapeutics, glitazones were the first class, influencing PPAR-γ, yet a range of adverse effects were reported regarding the use of PPAR-γ full agonists. Agents having partial PPAR-γ agonistic effect or selectively modulate PPAR-γ transactivity have been introduced. Nonetheless, most of these agents were abandoned at phase II clinical trials for unbalanced supra-therapeutic activation of the multireceptors. Despite clinical attentions towards advers effects, these clinical failures have defined the pharmacological boundaries for safer drug design. The emerging clinical pathway focuses on bifunctional hybridization to achieve glucose homeostasis through synergistic modulation rather than high-dose single-target activation. It was not until 2003 where G-protein-coupled receptor 40 (GPCR40), currently named as free fatty acid receptor-I (FFAR1), was discovered. A plausible FFAR1/PPAR-γ crosstalk has been suggested linking both receptors and insulin secretion. These findings triggered the development of several FFAR1 agonists. Nevertheless, and till the time of writing this review, limited studies proposed the synthesis of such hybrid molecules with only one reaching a regional market. The provided review deals with recent advances of both FFAR1 and PPAR-γ ligands in managing T2DM. Up-to-date medicinal chemistry description of FFAR1 and PPAR-γ modulators as well as each dual agonists have been provided with highlighted structural diversity and activity interlink for each main class.