2-[3-[2-[(25)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl] -1,2,3,4-tetrahydroisoquinoline: A potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV

Hsu Tsu, Xin Chen, Chiung Tong Chen, Shiow Ju Lee, Chung Nien Chang, Kuo His Kao, Mohane Selvaraj Coumar, Yen Ting Yeh, Chia Hui Chien, Hsin Sheng Wang, Ke Ta Lin, Ying Ying Chang, Ssu Hui Wu, Yuan Shou Chen, I. Lin Lu, Su Ying Wu, Ting Yueh Tsai, Wei Cheng Chen, Hsing Pang Hsieh, Yu Sheng ChaoWeir Torn Jiaang

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2- oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC50 values of <50 nM with excellent selectivity over both DPP8 (IC50 > 100 μM) and DPP-II (IC50 > 30 μM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.

Original languageEnglish
Pages (from-to)373-380
Number of pages8
JournalJournal of Medicinal Chemistry
Volume49
Issue number1
DOIs
Publication statusPublished - 2006 Jan 12

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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