Novel 2,7-Substituted (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: Peroxisome Proliferator-Activated Receptor γ Partial Agonists with Protein–Tyrosine Phosphatase 1B Inhibition
| Autor: | Arisa Kawahara, Kazuya Otake, Masaki Fukui, Hiroaki Shirahase, Satoru Azukizawa, Takeda Shigemitsu, Tatsuya Kitao |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
Agonist medicine.medical_specialty medicine.drug_class Phosphatase Peroxisome proliferator-activated receptor Mice Inbred Strains Partial agonist Diabetes Mellitus Experimental Rats Sprague-Dawley Mice Structure-Activity Relationship chemistry.chemical_compound Farglitazar Tetrahydroisoquinolines Internal medicine Drug Discovery medicine Animals Humans Hypoglycemic Agents Enzyme Inhibitors Receptor Protein Tyrosine Phosphatase Non-Receptor Type 1 chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure Tetrahydroisoquinoline Stereoisomerism General Chemistry General Medicine Rats PPAR gamma Endocrinology chemistry Rosiglitazone medicine.drug |
| Zdroj: | CHEMICAL & PHARMACEUTICAL BULLETIN. 63:998-1014 |
| ISSN: | 1347-5223 0009-2363 |
| Popis: | A novel series of 2,7-substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butylamine salt (13jE) was identified as a potent human peroxisome proliferator-activated receptor γ (PPARγ)-selective agonist (EC50=85 nM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC50=1.0 µM). Compound 13jE partially activated PPARγ, but not PPARα or PPARδ, and antagonized farglitazar, a full PPARγ agonist. Cmax after the oral administration of 13jE at 10 mg/kg was 28.6 µg/mL (53 µM) in male Sprague-Dawley (SD) rats. Repeated administration of 13jE and rosiglitazone for 14 d at 10 mg/kg/d decreased plasma glucose and triglyceride levels significantly in male KK-A(y) mice. Rosiglitazone, but not 13jE, significantly increased the plasma volume and liver weight. In conclusion, 13jE showed stronger hypoglycemic and hypolipidemic effects and weaker hemodilution and hepatotoxic effects than rosiglitazone, suggesting that its safer efficacy may be due to its partial PPARγ agonism and PTP-1B inhibition. |
| Databáze: | OpenAIRE |
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