2-Acyl-tetrahydroisoquinoline-3-carboxylic Acids: Lead compounds with triple actions, peroxisome proliferator-activated receptor α/γ agonist and protein-tyrosine phosphatase 1B inhibitory activities

Abstract

2-Acyl-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2,4-Hexadienoyl)-7-[2-(5-methyl- 2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14) showed peroxisome proliferator-activated receptor γ (PPARγ ) and PPARα agonist activities and protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activities. PPARγ agonist activity of 14 was comparable to that of rosiglitazone, and PTP-1B inhibitory activity was about 10-fold weaker than that of ertiprotafib, a PTP-1B inhibitor. Compound 14 showed high oral absorption in rats and potent hypoglycemic effects in KK-Ay mice. In conclusion, 14 would be an excellent lead compound for a new type of anti-diabetic drug with triple actions. © 2011 Pharmaceutical Society of Japan.