In the failing heart the sympathetic nervous system (SNS) elevates catecholamine levels leading to stimulation of the β-adrenergic receptors (βars). Due to this increased signaling the βars become overstimulated resulting in desensitization via G-protein coupled receptor kinases (GRKs) and severe uncoupling. Specifically, GRK2 is elevated in heart failure and inhibition of GRK2 interrupts the internalization of the βars allowing the heart to regain stimulation from the SNS. Our lab identified the FDA approved serotonin reuptake inhibitor paroxetine as a GRK2 inhibitor. Furthermoe, paroxetine was shown to reverse cardiac remodeling, renormalize levels of catecholoamines and βars in the heart, and have cardio-protective effects up to two weeks post treatment in mice. Utilizing the structural motifs in combination with the previously reported potent and selective GRK2 inhibitor Takeda103A a library of hybrid inhibitors was designed and synthesized. This structure based drug design campaign produced several compounds with impressive potency and selectivity for GRK2 over other AGC kinases. The most selective inhibitor was CCG258208, with an IC50 for GRK2 of 30 nM and &gt;230-fold selectivity vs other GRK subfamilies and AGC kinases. At a dose of 0.1 µM CCG258208 resulted in a significant increase in mouse cardiomyocyte contractility. Short pharmacokinetic studies have revealed plasma level concentrations up to seven hours higher than the IC50 of CCG258208. This series of paroxetine based hybrid inhibitors show promise as potent and selective GRK2 inhibitors with potential in vivo utility.

Metamorphosis of paroxetine into a highly potent and selective GRK2 inhibitor via structure-based drug design

253rd National Meeting (2017)

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