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

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Otake K, Azukizawa S, Fukui M, Kunishiro K, Kamemoto H, Kanda M, Miike T, Kasai M, Shirahase H

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

Bioorg Med Chem. 2012 Jan 15;20(2):1060-75. doi: 10.1016/j.bmc.2011.11.035. Epub 2011 Dec 1.

PubMed ID

22197396 [ View in PubMed

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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 gamma (PPARgamma) selective agonist (EC(50)=0.03 muM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC(50)=1.18 muM). C(max) after oral administration of 14i at 10mg/kg was 2.2 mug/ml (4.5 muM) 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 PPARgamma and PTP-1B.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	120	N/A	N/A	Details