(S)-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

• Published in: Chemical & pharmaceutical bulletin Vol. 67; no. 11; pp. 1211 - 1224
• Main Authors: Morishita, Ko, Miike, Tomohiro, Takeda, Shigemitsu, Fukui, Masaki, Ito, Yuma, Kitao, Tatsuya, Ozawa, Shin-ichiro, Hirono, Shuichi, Shirahase, Hiroaki
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.11.2019; Pharmaceutical Soc Japan
• Subjects: Administration, Oral; adverse effect; Animals; Blood Glucose - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Crystallography, X-Ray; diabetes; Diabetes Mellitus, Experimental - drug therapy; Female; Humans; Hyperglycemia - drug therapy; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Insulin Resistance; Life Sciences & Biomedicine; Male; Mice; Mice, Transgenic; Molecular Docking Simulation; Molecular Structure; partial agonist; peroxisome proliferator-activated receptor γ; Pharmacology & Pharmacy; Physical Sciences; PPAR gamma - agonists; Rats; Rats, Sprague-Dawley; Science & Technology; tetrahydroisoquinoline; Tetrahydroisoquinolines - administration & dosage; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - pharmacology; DESIGN; PROTEIN; INT131; SERIES; ALPHA/GAMMA DUAL AGONISTS; ALPHA; DISCOVERY; ISSUES; partial agonist; adverse effect; tetrahydroisoquinoline; MODULATOR; peroxisome proliferator-activated receptor gamma; diabetes; insulin resistance; BINDING; peroxisome proliferator-activated receptor γ
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c19-00541

A novel series of 2,6,7-substituted 3-unsubstituted 1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to find a peroxisome proliferator-activated receptor γ (PPARγ) partial agonist. Among the derivatives, (E)-7-[2-(cyclopent-3-eny)-5-methyloxazol-4-ylmethoxy]-2-[3-(2-furyl)acryloyl]-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydroisoquinoline (20g) exhibited potent partial agonist activity (EC50 = 13 nM, maximal response 30%) and very weak protein tyrosine phosphatase 1B (PTP1B) inhibition (IC50 = 1100 nM), indicating a selective PPARγ partial agonist. A computational docking calculation revealed that 20g bound to PPARγ in a similar manner to that of known partial agonists. In male and female KK-Ay mice with insulin resistance and hyperglycemia, 20g at 30 mg/kg for 7 d significantly reduced plasma glucose levels, but not triglyceride levels. The effects of 20g were similar to those of pioglitazone at 10 mg/kg. In conclusion, the 2,6,7-substituted 1,2,3,4-tetrahydroisoquinoline with an acidic group at the 6-position provides a novel scaffold for selective PPARγ partial agonists and 20g exerted anti-diabetic effects via the partial activation of PPARγ.