title: Insulin sensitization by a novel partial peroxisome proliferator-activated receptor γ agonist with protein tyrosine phosphatase 1B inhibitory activity in experimental osteoporotic rats.
abstract: 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 PPARγ 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.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kubo
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukui
authors.forename: Yuma
authors.initials: Y
authors.lastname: Ito
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kitao
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shirahase
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoneda
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000960:Hypolipidemic Agents; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology; D015663:Osteoporosis, Postmenopausal / Q000209:etiology*; D010052:Ovariectomy; D010080:Oxazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D051381:Rats; D011916:Rats, Inbred F344; D011972:Receptor, Insulin / Q000378:metabolism*; D012306:Risk; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: C000592277:7-(2-(2-(2-cyclopentylvinyl)-5-methyloxazol-4-yl)-ethoxy)-2-(2,4-hexadienoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007546:Isoquinolines; D010080:Oxazoles; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1