Title: Novel (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: peroxisome proliferator-activated receptor ## selective agonists with protein-tyrosine phosphatase 1B inhibition.

Abstract: 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 ## (PPAR##) selective agonist (EC(50)=0.03 ##M) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC(50)=1.18 ##M). C(max) after oral administration of 14i at 10mg/kg was 2.2 ##g/ml (4.5 ##M) in male SD rats. Repeated administration of 14i and rosiglitazone for 14 days dose-dependently decreased plasma glucose levels, ED(50)=4.3 and 23 mg/kg/day, respectively, in male KK-A(y) mice. In female SD rats, repeated administration of 14i at 12.5-100mg/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 25mg/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 PPAR## and PTP-1B.
(PMID: 22197396)

Putative Target:

ChEMBL Target ID: 50597
Target Type: ORGANISM
Pref Name: Rattus norvegicus
Organism: Rattus norvegicus
Tax ID: 10116
Confidence: Target assigned is non-molecular
Relationship Type: Non-molecular target assigned

ChEMBL Assay Type: Functional

ChEMBL Assay Data Source: Scientific Literature