Aryl- and heteroaryl-substituted aminobenzo[a]quinolizines as dipeptidyl peptidase IV inhibitors

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1106-8. doi: 10.1016/j.bmcl.2009.12.025. Epub 2009 Dec 6.

Abstract

Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors* / chemistry*
  • Dipeptidyl-Peptidase IV Inhibitors* / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors* / pharmacology
  • Humans
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology
  • Quinolizines / chemistry*
  • Quinolizines / metabolism
  • Quinolizines / pharmacology
  • Rats
  • Rats, Zucker

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Protease Inhibitors
  • Quinolizines
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4

Associated data

  • PDB/3KWJ