Receptor

Insulin sensitizing and adverse effects of KY-201, a novel PPAR  agonist, in female KK-A y mice and ovariectomized (OVX) rats were compared with those of rosiglitazone. In female KK-A y mice, repeated administration of KY-201 10 and 30 mg/kg/day for 4 weeks showed weaker adverse effects such as increase in heart weights and decrease in hematocrit and bone mineral density (BMD) than rosiglitazone. In OVX rats after 6 weeks administration at 3 and 10 mg/kg/day, the serum NEFA reducing effects of KY-201 were similar to those of rosiglitazone. KY-201 had no effects on body weight gain, blood volume, heart or adipose weights, while rosiglitazone at 10 mg/kg/day increased these parameters. Rosiglitazone, but not KY-201 strongly decreased BMD and increased fat in marrow. In 3T3-L1 cells and ST-2 cells, KY-201 showed a PPAR  partial agonist activity. KY-201 reduced osteoblast differentiation in bone marrow-derived mesenchymal stem cells (BMSCs) and increased adipocyte differentiation 3T3-L1 cells and BMSCs less potently than rosiglitazone in BMSCs. KY-201, but not rosiglitazone increased phosphorylation of the insulin receptor in HepG2 cells probably via its PTP1B inhibitory activity. These results show that KY-201 is a safer insulin sensitizing drug due to the combination of PPAR  partial activation and PTP1B inhibition.