Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group

Takashi Kondo, Takahiro Nekado, Isamu Sugimoto, Kenya Ochi, Shigeyuki Takai, Atsushi Kinoshita, Akira Hatayama, Susumu Yamamoto, Katsuya Kishikawa, Hisao Nakai, Masaaki Toda

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


A series of (4β-substituted)-l-prolylpyrrolidine analogs lacking the electrophilic nitrile function were synthesized and their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and duration of ex vivo activity were evaluated. Structural optimization of a N-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine analog 8, which was found by high-speed analog synthesis, was carried out to improve the potency and duration of action. A representative compound 26 was evaluated to assess its effect on the plasma glucose level after the oGTT (oral glucose tolerance test) in normal rats. Structure-activity relationships (SAR) are also presented.

Original languageEnglish
Pages (from-to)1613-1631
Number of pages19
JournalBioorganic and Medicinal Chemistry
Issue number4
Publication statusPublished - 2008 Feb 15
Externally publishedYes


  • (4β-Substituted)-l-prolylpyrrolidine
  • 1,2,4-Thiadiazol-5-yl-piperazine
  • DPP-IV inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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