PPAR Pan-Agonists

PPAR ligands with the ability to simultaneously activate all three receptor isotypes have the potential to address the adverse metabolic and cardiovascular liabilities associated with T2D, with concomitant reduction of the common side-effects associated with the PPARy agonists. 

Sodelglitazar (GW-677954) is a PPAR pan-agonist in phase II clinical trials for the treatment of T2D [74]. While published data is limited, this molecule is more active on PPAR8 compared to PPARa and PPARy (EC50 values of 1.3, 40 and 63 nM, respectively) and is efficacious in diabetic and hyperlipidemic rat models. 

Potent PPAR pan-agonists have been discovered recently through SAR studies around a series of indanylacetic acid derivatives [75], The lead molecule in this series, 34r, has EC50 values of 101,4.0 and 42 nM in assays that measure PPARa, PPAR8 and PPARy activity, respectively. When tested in dyslipidemic and diabetic rodent models, 34r was shown to have better therapeutic potential than known PPARy agonists. 

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