Heart failure is one of the leading causes of death in the Western world with a 50% mortality rate after five years. In the failing heart catecholamine levels are increased leading to stimulation of the �-adrenergic receptors. As a result, signaling of these receptors is increased. G-protein coupled receptor kinases (GRKs) regulate the �-adrenergic receptors through the process of desensitization. Elevated levels of G-protein coupled receptor kinase 2 (GRK2) have been found in cardiac muscle of animal models subjected to transverse aortic constriction. In addition, inhibition of GRK2 using a peptide inhibitor and through gene knockout has been shown to have cardioprotective effects in mice models. Previously, a small molecule inhibitor, the FDA approved selective serotonin reuptake inhibitor, paroxetine, was shown to inhibit GRK2 and improve cardiac performance in animal models. Through the use of structure based drug design we have made a library of paroxetine derivatives that have shown potency and selectivity for GRK2.

Development of selective GRK2 inhibitors for the treatment of heart failure

248th National Meeting (2014)

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