Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1

Nat Commun. 2013;4:1953. doi: 10.1038/ncomms2953.

Abstract

The anti-fibrotic, vasodilatory and pro-angiogenic therapeutic properties of recombinant relaxin peptide hormone have been investigated in several diseases, and recent clinical trial data has shown benefit in treating acute heart failure. However, the remodelling capacity of these peptide hormones is difficult to study in chronic settings because of their short half-life and the need for intravenous administration. Here we present the first small-molecule series of human relaxin/insulin-like family peptide receptor 1 agonists. These molecules display similar efficacy as the natural hormone in several functional assays. Mutagenesis studies indicate that the small molecules activate relaxin receptor through an allosteric site. These compounds have excellent physical and in vivo pharmacokinetic properties to support further investigation of relaxin biology and animal efficacy studies of the therapeutic benefits of relaxin/insulin-like family peptide receptor 1 activation.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Cyclic AMP / metabolism
  • Drug Evaluation, Preclinical / methods*
  • Drug Stability
  • Electric Impedance
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Hydrogen Bonding
  • Mice
  • Molecular Conformation
  • Molecular Sequence Data
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Peptide / agonists*
  • Receptors, Peptide / chemistry
  • Receptors, Peptide / metabolism
  • Relaxin / pharmacology
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Transfection
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • RXFP1 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Small Molecule Libraries
  • Vascular Endothelial Growth Factor A
  • Relaxin
  • Cyclic AMP

Associated data

  • PubChem-Substance/162211056
  • PubChem-Substance/162211057
  • PubChem-Substance/162211058
  • PubChem-Substance/162211059
  • PubChem-Substance/162211060
  • PubChem-Substance/162211061
  • PubChem-Substance/162211062
  • PubChem-Substance/162211063