A Novel Series of (S)-2,7-Substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acids: Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists with Protein-Tyrosine Phosphatase 1B Inhibitory Activity

Kazuya Otake; Satoru Azukizawa; Masaki Fukui; Michiko Shibabayashi; Hikaru Kamemoto; Tomohiro Miike; Kazuyoshi Kunishiro; Masayasu Kasai; Hiroaki Shirahase

doi:10.1248/cpb.59.1233

Regular Articles

A Novel Series of (S)-2,7-Substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acids: Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists with Protein-Tyrosine Phosphatase 1B Inhibitory Activity

Kazuya Otake, Satoru Azukizawa, Masaki Fukui, Michiko Shibabayashi, Hikaru Kamemoto, Tomohiro Miike, Kazuyoshi Kunishiro, Masayasu Kasai, Hiroaki Shirahase

Author information

Kazuya Otake
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
Satoru Azukizawa
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
Masaki Fukui
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
Michiko Shibabayashi
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
Hikaru Kamemoto
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
Tomohiro Miike
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
Kazuyoshi Kunishiro
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
Masayasu Kasai
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
Hiroaki Shirahase
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.

Keywords: peroxisome proliferator-activated receptor, diabetes, hypoglycemic effect, tetrahydroisoquinoline derivative, protein-tyrosine phosphatase 1B, KK-A^y mouse

JOURNAL FREE ACCESS

2011 Volume 59 Issue 10 Pages 1233-1242

DOI https://doi.org/10.1248/cpb.59.1233

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Abstract

Novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14c) was identified as a peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist. The transactivation activity of 14c was comparable to that of rosiglitazone in human PPARγ (EC₅₀=0.14 μM) and was much higher than in human PPARα (EC₅₀=0.20 μM). In addition, 14c, but not rosiglitazone, showed human protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activity (IC₅₀=1.85 μM). 14c showed about 10-fold stronger hypoglycemic and hypotriglyceridemic effects than rosiglitazone by repeated application for 14 d in male KK-A^y mice. Furthermore, 14c, but not rosiglitazone, increased hepatic peroxisome acyl CoA oxidase activity at 30 mg/kg/d for 7 d in male Syrian hamsters, probably due to its PPARα agonist activity. 14c did not affect plasma volume at 100 mg/kg/d for 14 d in male ICR mice, while rosiglitazone significantly increased it. In conclusion, 14c is a promising candidate for an efficacious and safe anti-diabetic drug with triple actions as a PPARα/γ dual agonist with PTP-1B inhibitory activity.

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