Design of selective peptidomimetic agonists for the human orphan receptor BRS-3

J Med Chem. 2003 May 8;46(10):1918-30. doi: 10.1021/jm0210921.

Abstract

New tool substances may help to unravel the physiological role of the human orphan receptor BRS-3 and its possible use as a drug target for the treatment of obesity and cancer. In continuation of our work on BRS-3, the solid- and solution-phase synthesis of a library of low molecular weight peptidomimetic agonists based on the recently developed short peptide agonist 4 is described. Functional potencies of the compounds were determined measuring calcium mobilization in a fluorometric imaging plate reader (FLIPR) assay. Focusing on the N-terminus, the d-Phe-Gln moiety of 4 was modified in a combinatorial SAR-oriented medicinal chemistry approach. With the incorporation of N-arylated glycine and alanine building blocks azaglycine, piperazine, or piperidine and the synthesis of semicarbazides and semicarbazones, a number of highly potent and selective compounds with a reduced number of peptide bonds were obtained, which also should have enhanced metabolic stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • CHO Cells
  • Calcium / metabolism
  • Combinatorial Chemistry Techniques
  • Cricetinae
  • Humans
  • Molecular Mimicry
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Peptides / chemistry*
  • Receptors, Bombesin / agonists*
  • Receptors, Bombesin / antagonists & inhibitors
  • Semicarbazides / chemical synthesis
  • Semicarbazides / chemistry
  • Semicarbazides / pharmacology
  • Semicarbazones / chemical synthesis
  • Semicarbazones / chemistry
  • Semicarbazones / pharmacology
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • Oligopeptides
  • Peptides
  • Receptors, Bombesin
  • Semicarbazides
  • Semicarbazones
  • bombesin receptor subtype 3
  • phenylalanyl-glutaminyl-tryptophan 1-(2-phenylethyl)amide
  • Calcium