Synthesis and biological evaluation of novel benzyl-substituted (S)-phenylalanine derivatives as potent dipeptidyl peptidase 4 inhibitors

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• 作者：Yang Liu ; Meimei Si ; Li Tang ; Shihao Shangguan ; Haoshu Wu ; Jia Li ; Peng Wu ; Xiaodong Ma ; Tao Liu ; Yongzhou Hu
• 关键词：Dipeptidyl peptidase 4 inhibitors ; Type 2 diabetes ; 1 ; 2 ; 3-Triazole ; (S)-Phenylalanine derivatives ; Selectivity
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 September, 2013
• 年：2013
• 卷：21
• 期：18
• 页码：5679-5687
• 全文大小：759 K

文摘

A series of novel benzyl-substituted (S)-phenylalanine derivatives were synthesized and evaluated for their dipeptidyl peptidase 4 (DPP-4) inhibitory activity and selectivity. It was found that most synthesized target compounds were potent DPP-4 inhibitors with IC₅₀ values in 3.79-25.52 nM, which were significantly superior to that of the marketed drug sitagliptin. Furthermore, the 4-fluorobenzyl substituted phenylalanine derivative 6g not only displayed the potent DPP-4 inhibition with an IC₅₀ value of 3.79 nM, but also showed better selectivity against DPP-4 over other related enzymes including DPP-7, DPP-8, and DPP-9. In an oral glucose tolerance test (OGTT) in normal Sprague Dawley rats, compound 6g reduced blood glucose excursion in a dose-dependent manner.