Novel 2,7-Substituted (<i>S</i>)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: Peroxisome Proliferator-Activated Receptor γ Partial Agonists with Protein–Tyrosine Phosphatase 1B Inhibition

Abstract

A novel series of 2,7-substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-yl] methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butylamine salt (13jE) was identified as a potent human peroxisome proliferator-activated receptor γ (PPARγ)-selective agonist (EC 50 85 nM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC 50 1.0 µM). Compound 13jE partially activated PPARγ, but not PPARα or PPARδ, and antagonized farglitazar, a full PPARγ agonist. C max after the oral administration of 13jE at 10 mg/kg was 28.6 µg/mL (53 µM) in male Sprague-Dawley (SD) rats. Repeated administration of 13jE and rosiglitazone for 14 d at 10 mg/kg/d decreased plasma glucose and triglyceride levels significantly in male KK-A y mice. Rosiglitazone, but not 13jE, significantly increased the plasma volume and liver weight. In conclusion, 13jE showed stronger hypoglycemic and hypolipidemic effects and weaker hemodilution and hepatotoxic effects than rosiglitazone, suggesting that its safer efficacy may be due to its partial PPARγ agonism and PTP-1B inhibition.

(<i>S</i>)-1,2,3,4-Tetrahydroisoquinoline Derivatives Substituted with an Acidic Group at the 6-Position as a Selective Peroxisome Proliferator-Activated Receptor γ Partial Agonist

“…We previously reported various types of PPARγ agonists using the same scaffold, 1,2,3,4-tetrahydroisoquinoline 3-calboxylic acid: a selective PPARγ full agonist, PPARγ full agonist with protein tyrosine phosphatase 1B (PTP1B) inhibition, PPARα/γ dual agonist with PTP1B inhibition, and PPARγ partial agonist with PTP1B inhibition. 25,26,[29][30][31] PTP1B negatively regulates the insulin signal and its overexpression has been implicated in insulin resistance; thus, the inhibition of PTP1B is expected to exert synergistic effects with PPARγ activation on insulin sensitization. [32][33][34] One of the 1,2,3,4-tetrahydroisoquinoline 3-calboxylic acids with PPARα/γ agonist and PTP1B inhibitory activities has been reported to exhibit effective antidiabetic activities with high safety, 35) and this may be due to its weak PPARγ activation and PTP1B inhibition.…”

2-Acyl-3-carboxyl-tetrahydroisoquinoline Derivatives: Mixed-Type PTP1B Inhibitors without PPARγ Activation

“…We previously reported various 3-carboxyl-tetrahydroisoquinoline derivatives with PPARγ agonist activities ( Fig. 1): a 2-alkyl-3-carboxyl-7-phenyloxazolyl-tetrahydroisoquinoline derivative with PPARγ full agonist activity, 37) a 2-acyl-3-carboxyl-7-alkenyloxazolyl-tetrahydroisoquinoline derivative with PPARγ full agonist activity and PTP1B inhibition (KY-699), 16) a 2-acyl-3-carboxyl-7-cycloalkenyloxazol-tetrahydroisoquinoline derivative with PPARγ and PPARα dual agonist activity and PTP1B inhibition (KY-601), 15) and a 2-acyl-3-carboxyl-7-(bulky substituent) oxazolyl-tetrahydroisoquinoline derivative with partial PPARγ agonist activity and PTP1B inhibition (KY-755). 17) In these studies, we found that substituents on the oxazole influenced PPARγ agonist activity, and an aliphatic substituent was preferable for PTP1B inhibitory activity.…”

“…We previously reported a novel series of 2-acyl-3-carboxyl-tetrahydroisoquinoline derivatives with potent PPARγ activation and weak PTP1B inhibition. [14][15][16][17] However, even weak PPARγ activation may cause side effects in PPARγ agonist-sensitive patients.…”

Novel Non-carboxylate Benzoylsulfonamide-Based Protein Tyrosine Phosphatase 1B Inhibitors with Non-competitive Actions

“…13) We previously demonstrated that a series of 3-carboxyl tetrahydroisoquinoline derivatives exhibited PPARγ agonist activities and weak PTP1B inhibitory activities. [14][15][16][17] Carboxyl types of inhibitors appear to compete with the substrate at the catalytic site, resulting in relatively low PTP1B selectivity because the catalytic site is similar among PTPs. 11,18) Although JTT-551 with a carboxyl moiety exhibited modest activity and antidiabetic effects in diabetic mice, clinical development was suspended possibly due to low efficacy in patients.…”