Design, synthesis, and characterization of fatty acid derivatives of a dimeric peptide-based postsynaptic density-95 (PSD-95) inhibitor

J Med Chem. 2015 Feb 12;58(3):1575-80. doi: 10.1021/jm501755d. Epub 2015 Jan 30.

Abstract

Dimeric peptide-based inhibitors of postsynaptic density-95 (PSD-95) can reduce ischemic brain damage and inflammatory pain in rodents. To modify the pharmacokinetic profile, we designed a series of fatty acid linked dimeric ligands, which potently inhibits PSD-95 and shows improved in vitro blood plasma stability. Subcutaneous administration in rats showed extended stability and sustained release of these ligands. This can facilitate new pharmacological uses of PSD-95 inhibitors and further exploration of PSD-95 as a drug target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disks Large Homolog 4 Protein
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Fatty Acids / chemical synthesis
  • Fatty Acids / chemistry
  • Fatty Acids / pharmacology*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Ligands
  • Membrane Proteins / antagonists & inhibitors*
  • Molecular Structure
  • Peptides / chemistry*
  • Rats
  • Structure-Activity Relationship

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Fatty Acids
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • Peptides