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) γ 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 pparg 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 pparγ 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 pparγ 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. © 2014 the japanese pharmacological society.