Design, synthesis, and biological evaluation of novel thiazolidinediones as PPARγ/FFAR1 dual agonists

• PPARγ and FFAR1 are valid targets for the management of type 2 diabetes.
• Some thiazolidinediones (PPAR ligands) could activate FFAR1 with micromolar potency.
• In this study, nineteen dual PPARγ/FFAR1 agonists were designed.
• The design depends on using TZD head with diverse privileged structures.
• Nine compounds showed promising dual activity.

Diabetes mellitus is a chronic metabolic disorder that affects more than 180 million people worldwide. Peroxisome proliferator activated receptors (PPARs) are a group of nuclear receptors that have been targeted by the thiazolidinedione (TZD) class of compounds for the management of type II diabetes. PPARγ is known to regulate adipogenesis and glucose metabolism. Another emerging target for the design of antidiabetic agents is the free fatty acid receptor 1 (FFAR1), previously known as GPR40. Agonists of this receptor were found to enhance insulin secretion in diabetic patients. It has been reported that some thiazolidinediones (TZDs) activate FFAR1 with micromolar potency. In this study, based on docking studies into the crystal structure of PPARγ and a homology model of FFAR1, nineteen compounds were designed, synthesized, and biologically tested for agonistic activity on both receptors. Nine compounds showed promising dual activity, with two compounds, 11a and 5b, having affinities in the low micromolar range on both targets. These molecules represent the first antidiabetic agents that could act as insulin sensitizers as well as insulin secretagogues.

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