Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors

Eur J Med Chem. 2013 Nov;69:384-92. doi: 10.1016/j.ejmech.2013.08.039. Epub 2013 Sep 13.


G protein-coupled receptor kinase 2 (GRK2) is a relevant signaling node of the cellular transduction network, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Emerging evidence suggests that GRK2 is up regulated in pathological situations such as heart failure, hypertrophy and hypertension, and its inhibition offers a potential therapeutic solution to these diseases. We explored the GRK2 inhibitory activity of a library of cyclic peptides derived from the HJ loop of G protein-coupled receptor kinases 2 (GRK2). The design of these cyclic compounds was based on the conformation of the HJ loop within the X-ray structure of GRK2. One of these compounds, the cyclic peptide 7, inhibited potently and selectively the GRK2 activity, being more active than its linear precursor. In a cellular system, this peptide confirms the beneficial signaling properties of a potent GRK2 inhibitor. Preferred conformations of the most potent analog were investigated by NMR spectroscopy.

Keywords: 2,2,4,6,7–pentamethyldihydro benzofuran-5-sulfonyl; 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate; 9-fluorenyl-methoxycarbonyl; ATP; Cardiovascular system; Cyclic peptides; DCM; DIPEA; DMF; DPC; EDTA; EGTA; ESI; Ethylene diamine tetraacetic acid; Fmoc; GRK2 inhibitors; HBTU; HOBt; LCQ; N,N-diisopropylethyl-amine; N,N-dimethylformamide; N-hydroxy-benzotriazole; NMR conformational analysis; Pbf; Pr(3)SiH or TIS; RP-HPLC; SAR; TFA; Trt; adenosine triphosphate; cAMP; cyclic adenosine monophosphate; dichloromethane; dodecylphosphocholine; electrospray ionization; ethylene glycol tetraacetic acid; liquid chromatography quadrupole mass spectrometry; reversed-phase high performance liquid chromatography; structure–activity relationship; trifluoroacetic acid; triisopropylsilane; trityl.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • G-Protein-Coupled Receptor Kinase 2 / antagonists & inhibitors*
  • G-Protein-Coupled Receptor Kinase 2 / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship


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