Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy

Life Sci Alliance. 2019 Feb 11;2(1):e201800186. doi: 10.26508/lsa.201800186. Print 2019 Feb.

Abstract

Cardiomyopathy is a leading cause of death for Duchenne muscular dystrophy. Here, we find that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can share common ligands but play distinct roles in dystrophic heart and skeletal muscle pathophysiology. Comparisons of their ligand structures indicate that the Δ9,11 modification of the first-in-class drug vamorolone enables it to avoid interaction with a conserved receptor residue (N770/N564), which would otherwise activate transcription factor properties of both receptors. Reporter assays show that vamorolone and eplerenone are MR antagonists, whereas prednisolone is an MR agonist. Macrophages, cardiomyocytes, and CRISPR knockout myoblasts show vamorolone is also a dissociative GR ligand that inhibits inflammation with improved safety over prednisone and GR-specific deflazacort. In mice, hyperaldosteronism activates MR-driven hypertension and kidney phenotypes. We find that genetic dystrophin loss provides a second hit for MR-mediated cardiomyopathy in Duchenne muscular dystrophy model mice, as aldosterone worsens fibrosis, mass and dysfunction phenotypes. Vamorolone successfully prevents MR-activated phenotypes, whereas prednisolone activates negative MR and GR effects. In conclusion, vamorolone targets dual nuclear receptors to treat inflammation and cardiomyopathy with improved safety.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aldosterone / chemistry
  • Aldosterone / pharmacology
  • Aldosterone / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • CRISPR-Associated Protein 9 / genetics
  • Cardiomyopathies / drug therapy*
  • Computer Simulation
  • Disease Models, Animal
  • Eplerenone / chemistry
  • Eplerenone / pharmacology
  • Eplerenone / therapeutic use
  • Gene Knockout Techniques
  • Hydrogen Bonding
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mineralocorticoid Receptor Antagonists / chemistry
  • Mineralocorticoid Receptor Antagonists / pharmacology
  • Mineralocorticoid Receptor Antagonists / therapeutic use*
  • Muscular Dystrophy, Duchenne / drug therapy
  • Myocarditis / drug therapy*
  • Myocarditis / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Prednisolone / chemistry
  • Prednisolone / pharmacology
  • Prednisolone / therapeutic use
  • Pregnadienediols / chemistry
  • Pregnadienediols / pharmacology
  • Pregnadienediols / therapeutic use*
  • RAW 264.7 Cells
  • Receptors, Glucocorticoid / chemistry
  • Receptors, Glucocorticoid / drug effects*
  • Receptors, Glucocorticoid / genetics
  • Receptors, Mineralocorticoid / agonists
  • Receptors, Mineralocorticoid / chemistry
  • Receptors, Mineralocorticoid / drug effects*

Substances

  • Anti-Inflammatory Agents
  • Mineralocorticoid Receptor Antagonists
  • Pregnadienediols
  • Receptors, Glucocorticoid
  • Receptors, Mineralocorticoid
  • VBP15 compound
  • Aldosterone
  • Eplerenone
  • Prednisolone
  • CRISPR-Associated Protein 9