MK-0767

The peroxisome proliferator-activated receptor gamma (PPAR-γ) is member of a large family of ligand-activated nuclear transcription factors.The first compounds reported as high-affinity PPAR-γ agonists were a class of antidiabetic agents known as thiazolidinediones or "glitazones".Quant. structure activity relationship (QSAR) analyses used to understand the structural factors responsible for PPAR-γ agonistic activity of some thiazolidinedione derivativesSeveral pharmacophore-based models indicated the importance of steric, hydrophobic, and hydrogen bond acceptor groups to agonistic activity.The 3D-QSAR anal. was carried out by PHASE program and a statistically reliable model with good predictive power (r² = 0.9702, q² = 0.8216) was achieved.The 3D-QSAR plots illustrated insights into the structure activity relationship of these compounds which may helps in the design and development of potent thiazolidinedione derivatives as antidiabetic agents.

The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the alpha-position and their evaluation for binding and activation of PPARalpha and PPARgamma are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARalpha/gamma dual agonist (EC(50)=0.013 and 0.061 microM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.