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

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

Author information

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.

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

PMID:
30006176
PMCID:
PMC6102074
DOI:
10.1016/j.ejmech.2018.06.008
[Indexed for MEDLINE]
Free PMC Article

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