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

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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)79-92
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume156
DOIs
StatePublished - Aug 5 2018

Keywords

  • 2-Acetamido-N-Phenylbenzamide
  • Antifibrotic
  • G-protein coupled receptor
  • Relaxin

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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