61892-67-9Relevant articles and documents
Novel (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: Peroxisome proliferator-activated receptor γ selective agonists with protein-tyrosine phosphatase 1B inhibition
Otake, Kazuya,Azukizawa, Satoru,Fukui, Masaki,Kunishiro, Kazuyoshi,Kamemoto, Hikaru,Kanda, Mamoru,Miike, Tomohiro,Kasai, Masayasu,Shirahase, Hiroaki
experimental part, p. 1060 - 1075 (2012/03/26)
A novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-2-[(2E,4E)-hexadienoyl]-7-(2-{5-methyl-2- [(1E)-5-methylhexen-1-yl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid (14i) was identified as a potent human peroxisome proliferator-activated receptor γ (PPARγ) selective agonist (EC 50 = 0.03 μM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC50 = 1.18 μM). Cmax after oral administration of 14i at 10 mg/kg was 2.2 μg/ml (4.5 μM) in male SD rats. Repeated administration of 14i and rosiglitazone for 14 days dose-dependently decreased plasma glucose levels, ED50 = 4.3 and 23 mg/kg/day, respectively, in male KK-Ay mice. In female SD rats, repeated administration of 14i at 12.5-100 mg/kg/day for 28 days had no effect on the hematocrit value (Ht) and red blood cell count (RBC), while rosiglitazone significantly decreased them from 25 mg/kg/day. In conclusion, 14i showed about a fivefold stronger hypoglycemic effect and fourfold or more weaker hemodilution effect than rosiglitazone, indicating that 14i is 20-fold or more safer than rosiglitazone. Compound 14i is a promising candidate for an efficacious and safe anti-diabetic drug targeting PPARγ and PTP-1B.
