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The novel GRK2 inhibitor 115h demonstrated highly potent activity (IC50 = 18 nM) and selectivity, potentiating β-adrenergic receptor-mediated cAMP accumulation in vitro.
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The discovery of compound 115h, a highly potent and selective GRK2 inhibitor, provides a novel preclinical candidate for the potential treatment of heart failure by potentiating β-adrenergic signaling.
A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.
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Okawa et al. (2017) studied Heart failure. GRK2 inhibitor 115h was evaluated on GRK2 inhibition (IC50 = 18 nM). The novel GRK2 inhibitor 115h demonstrated highly potent activity (IC50 = 18 nM) and selectivity, potentiating β-adrenergic receptor-mediated cAMP accumulation in vitro.
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