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

Therapeutic Approaches


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.


Wilson, Kenneth J; Xiao, Jingbo; Chen, Catherine; Huang, Zaohua; Agoulnik, Irina U; Ferrer-Alegre, Marc; Southall, Noel; Hu, Xin; Zheng, Wei; Xu, Xin; Wang, Amy; Myhr, Courtney; Barnaeva, Elena; George, Emmett R; Agoulnik, Alexander I; Marugan, Juan;


  • 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

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