title: Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1.
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.
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Xiao
authors.forename: Zaohua
authors.initials: Z
authors.lastname: Huang
authors.forename: Catherine Z
authors.initials: CZ
authors.lastname: Chen
authors.forename: Irina U
authors.initials: IU
authors.lastname: Agoulnik
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.forename: Raisa E
authors.initials: RE
authors.lastname: Jones
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Agoulnik
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004355:Drug Stability; D017097:Electric Impedance; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D018000:Receptors, Peptide / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D012065:Relaxin / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C417543:RXFP1 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D054852:Small Molecule Libraries; D042461:Vascular Endothelial Growth Factor A; D012065:Relaxin; D000242:Cyclic AMP