2-[3-[2-[(2S)-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

J Med Chem. 2006 Jan 12;49(1):373-80. doi: 10.1021/jm0507781.

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 IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose / drug effects
  • Dipeptidases / antagonists & inhibitors
  • Dipeptidyl Peptidase 4 / blood
  • Dipeptidyl Peptidase 4 / drug effects*
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors
  • Drug Evaluation, Preclinical
  • Drug Tolerance
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Glucose / administration & dosage
  • Glucose / antagonists & inhibitors
  • Humans
  • In Vitro Techniques
  • Isoquinolines / chemical synthesis
  • Isoquinolines / pharmacology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Molecular Conformation
  • Pyrrolidinones / chemical synthesis
  • Pyrrolidinones / pharmacology*
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Time Factors

Substances

  • 2-(3-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-3-methyl-1-oxobutyl)-1,2,3,4-tetrahydroisoquinoline
  • Blood Glucose
  • Enzyme Inhibitors
  • Isoquinolines
  • Pyrrolidinones
  • Dipeptidases
  • DPP9 protein, human
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • dipeptidyl peptidase II
  • DPP8 protein, human
  • Dipeptidyl Peptidase 4
  • Glucose