Novel (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: Peroxisome proliferator-activated receptor ¦Ã selective agonists with protein-tyrosine phosphatase 1B inhibition

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• 作者：Kazuya Otake ; Satoru Azukizawa ; Masaki Fukui ; Kazuyoshi Kunishiro ; Hikaru Kamemoto ; Mamoru Kanda ; Tomohiro Miike ; Masayasu Kasai ; Hiroaki Shirahase ; ^{shirahase@kyoto-pharm.co.jp}
• 关键词：RPSZQKFPURNXFI-MTIUZVMISA-N ; HYYXCKYRDBFMBH-ICVDDYDLSA-N ; AKXRQCXICDJIPB-ZOMMWANESA-N ; SNQXXUFDGAPQMX-WYPHMJFBSA-N ; ZWOZNKRLUBGDAD-XHKITAOQSA-N ; PKBVKAPKPOKITO-PRGXZJRWSA-N ; ZWXKSBKVMQADJG-PWANEJKLSA-N ; ISXUDGNVHDUHHC-AKISVASBSA-N ; FOLFRKHUARXLNX-AFBVSDSI
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：15 January, 2012
• 年：2012
• 卷：20
• 期：2
• 页码：1060-1075
• 全文大小：1163 K

文摘

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 ¦Ã (PPAR¦Ã) selective agonist (EC₅₀ = 0.03 ¦ÌM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC₅₀ = 1.18 ¦ÌM). C_max after oral administration of 14i at 10 mg/kg was 2.2 ¦Ìg/ml (4.5 ¦ÌM) in male SD rats. Repeated administration of 14i and rosiglitazone for 14 days dose-dependently decreased plasma glucose levels, ED₅₀ = 4.3 and 23 mg/kg/day, respectively, in male KK-A^y mice. In female SD rats, repeated administration of 14i at 12.5-100 mg/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 25 mg/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 PPAR¦Ã and PTP-1B.