Design and Synthesis of Dual Peroxisome Proliferator-Activated Receptors γ and δ Agonists as Novel Euglycemic Agents with a Reduced Weight Gain Profile

The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) γ/δ agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR γ/δ agonist profile (IC₅₀ = 19 nM/4 nM; EC₅₀ = 102 nM/6 nM for hPPARγ and hPPARδ, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.