4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV

Bioorg Med Chem Lett. 2007 May 15;17(10):2879-85. doi: 10.1016/j.bmcl.2007.02.066. Epub 2007 Feb 25.

Abstract

A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.

MeSH terms

  • Administration, Oral
  • Alanine / analogs & derivatives*
  • Alanine / chemistry
  • Alanine / pharmacology
  • Animals
  • Binding Sites
  • Biological Availability
  • Crystallography, X-Ray
  • Cyclohexanes / chemistry
  • Cyclohexanes / pharmacology*
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl-Peptidase IV Inhibitors*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glucose Tolerance Test
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemistry
  • Phenylalanine / pharmacology
  • Structure-Activity Relationship

Substances

  • 4-aminocyclohexylalanine
  • Cyclohexanes
  • Dipeptidyl-Peptidase IV Inhibitors
  • Enzyme Inhibitors
  • 4-aminophenylalanine
  • Phenylalanine
  • Dipeptidyl Peptidase 4
  • Alanine