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

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.
Kenneth J Wilson 1,  Jingbo Xiao 1,  Catherine Z Chen 1,  Zaohua Huang 2,  Irina U Agoulnik 2,  Marc Ferrer 1,  Noel Southall 1,  Xin Hu 1,  Wei Zheng 1,  Xin Xu 1,  Amy Wang 1,  Courtney Myhr 2,  Elena Barnaeva 1,  Emmett R George 1,  Alexander I Agoulnik 2,  Juan J Marugan 3
Affiliations

Affiliations

  • 1 NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • 2 Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, HLSI 419B, Miami, FL, 33199, USA.
  • 3 NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA. Electronic address: maruganj@mail.nih.gov.
PMID: 30006176 DOI: 10.1016/j.ejmech.2018.06.008
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.

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