Office of Technology Transfer – University of Michigan

G protein-coupled receptor kinase inhibitors to treat heart failure

Technology #6497

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Categories
Researchers
John J G Tesmer
Managed By
Ed Pagani
Assistant Director, Health Technologies 734-763-3558
Patent Protection
PCT Patent Application WO 2016/210403
Publications
Molecular Mechanism of Selectivity among G Protein-Coupled Receptor Kinase 2 Inhibitors
Mol Pharmacol. 2011 Aug;80(2):294-303. doi: 10.1124/mol.111.071522. Epub 2011 May 19., 2011
Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility
ACS Chem. Biol., 2012, 7 (11), pp 1830–1839, DOI: 10.1021/cb3003013, Publication Date (Web): August 10, 2012, 2012
Structural and functional analysis of g protein-coupled receptor kinase inhibition by paroxetine and a rationally designed analog
Mol Pharmacol. 2014 Feb;85(2):237-48. doi: 10.1124/mol.113.089631. Epub 2013 Nov 12., 2014
Molecular Basis for Small Molecule Inhibition of G Protein-Coupled Receptor Kinases
ACS Chem. Biol., Article ASAP, DOI: 10.1021/cb5003976, Publication Date (Web): July 1, 2014, 2014
Identification and Structure-Function Analysis of Subfamily Selective G Protein-Coupled Receptor Kinase Inhibitors
ACS Chem. Biol., Article ASAP, DOI: 10.1021/cb5006323, Publication Date (Web): September 19, 2014, 2014

Heart failure (also known as congestive heart failure) occurs when the heart becomes too weak to pump enough blood to meet the body’s oxygen requirements. In the United States, over 5 million people have heart failure, and the disease contributes to approximately 260,000 deaths (one in every nine deaths total) annually. In addition, heart failure costs the country an estimated $32 billion per year. Despite the growing number of cases, many attempts at developing improved heart failure treatments have failed. One promising approach may be to target G protein-coupled receptor kinase 2 (GRK2), which shows a two- to three-fold increase in activity during heart failure. In animal models, GRK2 inhibition or knockout has been shown to improve cardiac outcomes, making GRK2 an appealing target for potential heart failure therapeutics. However, previous GRK inhibitors have either had insufficient potency or selectivity or have had poor pharmacokinetic properties, preventing any further in vivo development. There is therefore a demand for an inhibitory molecule with high bioavailability (favorable pharmacokinetic properties) plus high potency and selectivity for GRK2.

Inhibitors integrate a paroxetine backbone to target GRK2 with high potency, selectivity, and bioavailability

Previous research has identified paroxetine as an inhibitor that is moderately potent and selective for GRK2 but has excellent pharmacokinetics and an ability to increase contractility of heart muscle both in vitro and in vivo. A second inhibitor has shown high potency and selectivity for GRK2 but poor bioavailability. To combine the pharmacokinetics of paroxetine with the potency and selectivity of the second inhibitor, a unique biochemical approach has synthesized hybrids of these molecules by taking advantage of common structural components within their respective GRK2-interacting regions. Over 50 hybrid analogs have been created with this strategy, and the most promising candidates have shown improved potency and selectivity compared with paroxetine alone. Paroxetine, under the trade name of Paxil, is already on the market for its role as a selective serotonin re-uptake inhibitor to treat depression and anxiety, but a modified paroxetine would have a higher molecular weight, limiting it from crossing the blood brain barrier. Therefore, if used to treat heart failure, the hybrid would avoid off-target effects in the brain. These pharmacokinetically favorable, paroxetine-based molecules with high potency and selectivity for GRK2 are attractive candidates for a much-needed heart failure treatment.

Applications

  • Development of candidate therapeutics for heart failure
  • Chemical probe to study GRK2 function in cells

Advantages

  • High bioavailability
  • High potency and selectivity
  • Avoids off-target effects