Abstract
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.
MeSH terms
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Crystallography, X-Ray
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Cytochrome P-450 CYP3A / metabolism
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Cytochrome P-450 CYP3A Inhibitors / chemical synthesis
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Cytochrome P-450 CYP3A Inhibitors / chemistry
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Cytochrome P-450 CYP3A Inhibitors / pharmacology
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Drug Design
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G-Protein-Coupled Receptor Kinase 2 / antagonists & inhibitors*
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HEK293 Cells
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Heart Failure / drug therapy*
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High-Throughput Screening Assays
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Humans
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Hydrazones / chemical synthesis
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Hydrazones / chemistry
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Hydrazones / pharmacology
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Protein Kinase C-alpha / antagonists & inhibitors
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology*
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Receptors, Adrenergic, beta / metabolism
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Structure-Activity Relationship
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Triazoles / chemical synthesis
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Triazoles / chemistry
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Triazoles / pharmacology*
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meta-Aminobenzoates / chemical synthesis
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meta-Aminobenzoates / chemistry
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meta-Aminobenzoates / pharmacology*
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rho-Associated Kinases / antagonists & inhibitors
Substances
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3-(((4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)-N-(2-(trifluoromethyl)benzyl)benzamide
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Cytochrome P-450 CYP3A Inhibitors
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Hydrazones
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Protein Kinase Inhibitors
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Pyridines
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Receptors, Adrenergic, beta
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Triazoles
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meta-Aminobenzoates
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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ROCK2 protein, human
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rho-Associated Kinases
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Protein Kinase C-alpha
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GRK2 protein, human
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G-Protein-Coupled Receptor Kinase 2