title: Synthesis and biological evaluation of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: a novel series of PPAR gamma agonists.
abstract: A novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-Benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (10, KY-021) was identified as a novel peroxisome proliferators-activated receptor (PPAR) gamma agonist, which showed potent activity in human PPAR gamma (EC50=11.8 nM). KY-021 reduced plasma glucose and triglyceride levels at 3 mg/kg/d for 7 d in male KK-Ay mice. KY-021 also decreased plasma triglyceride levels at 0.3-3 mg/kg/d for 6 d, and improved oral glucose tolerance at 1 and 3 mg/kg/d for 7 d in male Zucker fatty rats. Maximal plasma concentration of KY-021 after oral administration at 10 mg/kg was 6.6 microg/ml and 2.1 microg/ml in male ICR mice and male SD rats, respectively. Repeated oral administration of KY-021 at 30 mg/kg/d for 10 weeks had little toxicity in male SD rats. These results demonstrated that KY-021 has great potential as an efficacious and safe drug for diabetes.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Azukizawa
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kasai
authors.forename: Kenji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miike
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kunishiro
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kanda
authors.forename: Chisato
authors.initials: C
authors.lastname: Mukai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shirahase
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002855:Chromatography, Thin Layer; D003500:Cyclization; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008813:Mice, Inbred ICR; D010080:Oxazoles / Q000097:blood / Q000493:pharmacokinetics; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007202:Indicators and Reagents; D010080:Oxazoles; D047495:PPAR gamma; D044005:Tetrahydroisoquinolines; D014280:Triglycerides; C422415:farglitazar; C031270:1,2,3,4-tetrahydroisoquinoline carboxylic acid; D014443:Tyrosine