Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor

Bioorg Med Chem Lett. 2020 Dec 1;30(23):127602. doi: 10.1016/j.bmcl.2020.127602. Epub 2020 Oct 7.

Abstract

G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of β-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs.

Keywords: Cardiomyocytes; GRK2 inhibitor; Heart failure; Molecular modelling; Structure-based drug design; β-Adrenergic receptor.

MeSH terms

  • Animals
  • Enzyme Assays
  • G-Protein-Coupled Receptor Kinase 2 / antagonists & inhibitors*
  • G-Protein-Coupled Receptor Kinase 2 / metabolism
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Molecular Structure
  • Myocytes, Cardiac / drug effects
  • Phthalazines / chemical synthesis
  • Phthalazines / pharmacokinetics
  • Phthalazines / pharmacology*
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / metabolism
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Phthalazines
  • Protein Kinase Inhibitors
  • Quinazolines
  • GRK2 protein, human
  • G-Protein-Coupled Receptor Kinase 2