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

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Authors

External Institution(s)

  • University of Michigan, Ann Arbor
  • Temple University

Details

Original languageEnglish (US)
Pages (from-to)3052-3069
Number of pages18
JournalJournal of Medicinal Chemistry
Volume60
Issue number7
StatusPublished - Apr 13 2017
Peer-reviewedYes

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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Waldschmidt, HV, Homan, KT, Cato, MC, Cruz-Rodríguez, O, Cannavo, A, Wilson, MW, Song, J, Cheung, JY, Koch, WJ, Tesmer, JJG & Larsen, SD 2017, 'Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine', Journal of Medicinal Chemistry, vol. 60, no. 7, pp. 3052-3069. https://doi.org/10.1021/acs.jmedchem.7b00112