G protein-coupled receptor kinase 5 (GRK5) has been considered as a potential target for the treatment of
heart failure as it has been reported to be an important regulator of pathological
cardiac hypertrophy. To discover novel scaffolds that selectively inhibit GRK5, we have identified a novel small molecule inhibitor of GRK5, KR-39038 [7-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl) amino)-2-(2-chlorophenyl)-6-fluoroquinazolin-4(3H)-one]. KR-39038 exhibited potent inhibitory activity (IC50 value=0.02 μM) against GRK5 and significantly inhibited
angiotensin II-induced cellular
hypertrophy and HDAC5 phosphorylation in neonatal cardiomyocytes. In the pressure overload-induced
cardiac hypertrophy mouse model, the daily
oral administration of KR-39038 (30 mg/kg) for 14 days showed a 43% reduction in the left ventricular weight. Besides, KR-39038 treatment (10 and 30 mg/kg/ day, p.o.) showed significant preservation of cardiac function and attenuation of myocardial remodeling in a rat model of chronic
heart failure following coronary artery
ligation. These results suggest that potent GRK5 inhibitor could effectively attenuate both
cardiac hypertrophy and dysfunction in experimental
heart failure, and KR-39038 may be useful as an effective GRK5 inhibitor for
pharmaceutical applications.