A novel series of (S)-2,7-substituted-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acids: Peroxisome proliferator-activated receptor α/γ dual agonists with protein-tyrosine phosphatase 1B inhibitory activity

Abstract

Novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-methyloxazol-4-yl}ethoxy) -2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14c) was identified as a peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist. The transactivation activity of 14c was comparable to that of rosiglitazone in human PPARg (EC 50=0.14μM) and was much higher than in human PPARα (EC 50=0.20μM). In addition, 14c, but not rosiglitazone, showed human protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activity (IC 50=1.85μM). 14c showed about 10-fold stronger hypoglycemic and hypotriglyceridemic effects than rosiglitazone by repeated application for 14 d in male KK-A ymice. Furthermore, 14c, but not rosiglitazone, increased hepatic peroxisome acyl CoA oxidase activity at 30 mg/kg/d for 7 d in male Syrian hamsters, probably due to its PPARα agonist activity. 14c did not affect plasma volume at 100 mg/kg/d for 14 d in male ICR mice, while rosiglitazone significantly increased it. In conclusion, 14c is a promising candidate for an efficacious and safe anti-diabetic drug with triple actions as a PPARα/γ dual agonist with PTP-1B inhibitory activity. © 2011 Pharmaceutical Society of Japan.