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

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 gamma (PPAR gamma)-selective agonist (EC50=85nm) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC50=1.0 mu m). Compound 13jE partially activated PPAR gamma, but not PPAR alpha or PPAR delta, and antagonized farglitazar, a full PPAR gamma agonist. C-max after the oral administration of 13jE at 10 mg/kg was 28.6 mu g/mL (53 mu m) in male Sprague-Dawley (SD) rats. Repeated administration of 13jE and rosiglitazone for 14d 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 PPAR gamma agonism and PTP-1B inhibition.