Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1

Jingbo Xiao, Zaohua Huang, Catherine Z. Chen, Irina U. Agoulnik, Noel Southall, Xin Hu, Raisa E. Jones, Marc Ferrer, Wei Zheng, Alexander I. Agoulnik and Juan J. Marugan ()
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Jingbo Xiao: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
Zaohua Huang: Herbert Wertheim College of Medicine, Florida International University
Catherine Z. Chen: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
Irina U. Agoulnik: Herbert Wertheim College of Medicine, Florida International University
Noel Southall: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
Xin Hu: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
Raisa E. Jones: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
Marc Ferrer: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
Wei Zheng: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
Alexander I. Agoulnik: Herbert Wertheim College of Medicine, Florida International University
Juan J. Marugan: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health

Nature Communications, 2013, vol. 4, issue 1, 1-7

Abstract: Abstract The anti-fibrotic, vasodilatory and pro-angiogenic therapeutic properties of recombinant relaxin peptide hormone have been investigated in several diseases, and recent clinical trial data has shown benefit in treating acute heart failure. However, the remodelling capacity of these peptide hormones is difficult to study in chronic settings because of their short half-life and the need for intravenous administration. Here we present the first small-molecule series of human relaxin/insulin-like family peptide receptor 1 agonists. These molecules display similar efficacy as the natural hormone in several functional assays. Mutagenesis studies indicate that the small molecules activate relaxin receptor through an allosteric site. These compounds have excellent physical and in vivo pharmacokinetic properties to support further investigation of relaxin biology and animal efficacy studies of the therapeutic benefits of relaxin/insulin-like family peptide receptor 1 activation.

Date: 2013
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DOI: 10.1038/ncomms2953

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