title: 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.
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-Ay 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.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto, 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: Michiko
authors.initials: M
authors.lastname: Shibabayashi
authors.forename: Hikaru
authors.initials: H
authors.lastname: Kamemoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miike
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kunishiro
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kasai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shirahase
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002264:Carboxylic Acids / Q000737:chemistry; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D058990:Molecular Targeted Therapy; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077154:Rosiglitazone; D044005:Tetrahydroisoquinolines / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D002264:Carboxylic Acids; C413505:DPC 961; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D052999:Quinazolinones; D044005:Tetrahydroisoquinolines; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D017027:Protein Tyrosine Phosphatases