Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

The pharmacological profile of (S)-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-methyloxazol-4-yl}-ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (KY-201), a peroxisome proliferator-activated receptor (PPAR) gamma agonist, was compared with that of rosiglitazone in ovariectomized rats. The serum triglyceride and non-esterified fatty acid reducing effects of KY-201 at 3 and 10 mg/kg per day for 6 weeks were similar to those of rosiglitazone despite its weaker PPAR gamma agonistic activity. KY-201 had no effects on body weight gain, blood volume, or heart and adipose weights, while rosiglitazone at 10 mg/kg per day increased them. KY-201 had few effects on bone mineral density (BMD) or fat in marrow (FM), whereas rosiglitazone strongly decreased BMD and increased FM. The PPAR gamma agonistic activity of KY-201 was weaker than that of rosiglitazone in ST-2 cells, and KY-201 reduced osteoblast differentiation and increased adipocyte differentiation less potently than rosiglitazone in rat bone marrow-derived mesenchymal stem cells. KY-201, but not rosiglitazone inhibited protein tyrosine phosphatase 1B (PTP1B) and increased phosphorylation of the insulin receptor in HepG2 cells. These results suggest that the hypolipidemic effects of KY-201 are similar to those of rosiglitazone, but with less adverse effects, due to the combination of PPAR gamma partial activation and PTP1B inhibition. KY-201 would be useful for treatments of diabetic patients at high risk of osteoporosis, cardiovascular disease, and/or obesity.