Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine

  • J Med Chem. 2017 Apr 13;60(7):3052-3069. doi: 10.1021/acs.jmedchem.7b00112.
Helen V Waldschmidt  1  2 ,  Kristoff T Homan  1  2 ,  Marilyn C Cato  1  2 ,  Osvaldo Cruz-Rodríguez  1  2 ,  Alessandro Cannavo  1  2 ,  Michael W Wilson  1  2 ,  Jianliang Song  1  2 ,  Joseph Y Cheung  1  2 ,  Walter J Koch  1  2 ,  John J G Tesmer  1  2 ,  Scott D Larsen  1  2
Affiliations
  • 1. Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • 2. Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
PMID: 28323425 DOI: 10.1021/acs.jmedchem.7b00112
Abstract

In heart failure, the β-adrenergic receptors (βARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart, making them desirable therapeutic targets. The selective serotonin reuptake inhibitor, paroxetine, was previously identified as a GRK2 inhibitor. Utilizing a structure-based drug design approach, we modified paroxetine to generate a small compound library. Included in this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC50 of 30 nM against GRK2 and greater than 230-fold selectivity over Other GRKs and kinases. Furthermore, 14as showed a 100-fold improvement in cardiomyocyte contractility assays over paroxetine and a plasma concentration higher than its IC50 for over 7 h. Three of these inhibitors, including 14as, were additionally crystallized in complex with GRK2 to give insights into the structural determinants of potency and selectivity of these inhibitors.

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