Novel PDE9 inhibitors, KR39526 and KR39582, attenuate cardiac hypertrophy and fibrosis induced by pressure overload

Abstract

The natriuretic peptide and cyclic guanosine monophosphate (cGMP) cascade are promising therapeutic target for heart failure. This study evaluated the pharmacological properties and cardioprotective effects of novel phosphodiesterase 9 (PDE9) inhibitors, KR39526 and KR39582, in vitro and in vivo. The potency and selectivity of these compounds were assessed through PDE9 inhibitory activity and subfamily selectivity assays. Functional analyses in cardiomyocytes included calcium mobilization, cellular hypertrophy, and protein expression. The cardioprotective efficacy was investigated using a mouse model of pressure-overload-induced cardiac hypertrophy. KR39526 and KR39582 demonstrated potent PDE9A inhibitory activities (IC₅₀: 5 ± 2 nM and 0.4 ± 0.1 nM, respectively) with high selectivity. This inhibition led to concentration-dependent calcium influx through maintaining intracellular cGMP levels and significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy. Oral administration (50 mg·kg-1) of these compounds markedly attenuated cardiac hypertrophy and myocardial fibrosis induced by pressure overload. These results suggest that KR39526 and KR39582, as potent and selective PDE9A inhibitors, have strong potential for exerting anti-hypertrophic and anti-fibrotic effects in heart failure. These compounds can serve as valuable pharmacological tools to elucidate the roles of PDE9A signaling in heart failure pathophysiology and hold significant promise as potential therapeutic agents.