Design, Synthesis, and Evaluation of the Highly Selective and Potent G‑Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure

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.