Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors

J Med Chem. 2018 May 10;61(9):4263-4269. doi: 10.1021/acs.jmedchem.8b00488. Epub 2018 Apr 25.

Abstract

We report the development of macrocyclic melanocortin derivatives of MT-II and SHU-9119, achieved by modifying the cycle dimension and incorporating constrained amino acids in ring-closing. This study culminated in the discovery of novel agonists/antagonists with an unprecedented activity profile by adding pieces to the puzzle of the melanocortin receptor selectivity. Finally, the resulting 19- and 20-membered rings represent a suitable frame for the design of further therapeutic ligands as selective modulators of the melanocortin system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Amino Acids / chemistry*
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Macrocyclic Compounds / chemistry*
  • Molecular Docking Simulation
  • Peptidomimetics / chemistry*
  • Peptidomimetics / metabolism
  • Peptidomimetics / pharmacology*
  • Protein Conformation
  • Receptors, Melanocortin / chemistry
  • Receptors, Melanocortin / metabolism*
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Macrocyclic Compounds
  • Peptidomimetics
  • Receptors, Melanocortin