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

Yang Liu, Meimei Si, Li Tang, Shihao Shangguan, Haoshu Wu, Jia Li, Peng Wu, Xiaodong Ma, Tao Liu, Yongzhou Hu

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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 3.79–25.52nM, 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 3.79nM, 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.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry
Volume21
Issue number18
Pages (from-to)5679-5687
ISSN0968-0896
DOIs
Publication statusPublished - 2013
Externally publishedYes

Keywords

  • Dipeptidyl peptidase 4 inhibitors
  • Type 2 diabetes
  • 1,2,3-Triazole
  • (S)-Phenylalanine derivatives
  • Selectivity

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