Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors

G protein-coupled
receptors (GPCRs) are central to many physiological
processes. Regulation of this superfamily of receptors is controlled
by GPCR kinases (GRKs), some of which have been implicated in heart
failure. GSK180736A, developed as a Rho-associated coiled-coil kinase
1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized
in the active site. Guided by its binding pose overlaid with the binding
pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid
inhibitors was developed. This campaign produced several compounds
possessing high potency and selectivity for GRK2 over other GRK subfamilies,
PKA, and ROCK1. The most selective compound, 12n (CCG-224406),
had an IC50 for GRK2 of 130 nM, >700-fold selectivity
over
other GRK subfamilies, and no detectable inhibition of ROCK1. Four
of the new inhibitors were crystallized with GRK2 to give molecular
insights into the binding and kinase selectivity of this class of
inhibitors.