Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile

Eur J Med Chem. 2018 Aug 5:156:79-92. doi: 10.1016/j.ejmech.2018.06.008. Epub 2018 Jun 7.

Abstract

A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity study has been undertaken to optimize the potency, efficacy, and physical properties of the series, resulting in the identification of compound 65 (ML-290), which has excellent in vivo PK properties with high levels of systemic exposure. This series, exemplified by 65, has produced first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes.

Keywords: 2-Acetamido-N-Phenylbenzamide; Antifibrotic; G-protein coupled receptor; Relaxin.

MeSH terms

  • Animals
  • Benzamides / chemistry*
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology*
  • Cell Line
  • HEK293 Cells
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Humans
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Mice, Inbred C57BL
  • Models, Molecular
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Peptide / agonists*
  • Receptors, Peptide / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology
  • Transcriptome / drug effects*

Substances

  • Benzamides
  • RXFP1 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Small Molecule Libraries