title: Novel (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: peroxisome proliferator-activated receptor γ selective agonists with protein-tyrosine phosphatase 1B inhibition.
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 γ (PPARγ) selective agonist (EC(50)=0.03 μM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC(50)=1.18 μM). C(max) after oral administration of 14i at 10mg/kg was 2.2 μg/ml (4.5 μM) 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 PPARγ and PTP-1B.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd, 38, Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto 604-8444, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Otake
authors.forename: Satoru
authors.initials: S
authors.lastname: Azukizawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukui
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kunishiro
authors.forename: Hikaru
authors.initials: H
authors.lastname: Kamemoto
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kanda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miike
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kasai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shirahase
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C572012:2-(2,4-hexadienoyl)-7-(2-(5-methyl-2-(5-methylhexen-1-yl)oxazol-4-yl)ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D007004:Hypoglycemic Agents; D007546:Isoquinolines; D010080:Oxazoles; D047495:PPAR gamma; D044005:Tetrahydroisoquinolines; C031270:1,2,3,4-tetrahydroisoquinoline carboxylic acid; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1