Discovery of novel selective phosphodiesterase‑1 inhibitors for the treatment of acute myelogenous leukemia

[Display omitted] •Compound 6c exhibited an IC50 of 7.5 nM against PDE1, excellent selectivity towards other PDE subfamilies and rat liver microsome (RLM) metabolically stability (T1/2 = 41 min).•Compound 6c showed excellent anti-proliferative effects and induced apoptosis in AML cells,which through a mitochondria-dependent pathwayby decreasing the ratio of Bcl-2/Bax and increasing the cleaved caspase-3, 7, 9 and PARP.•This work provided promising lead compounds or chemical probes for investigating the biological functions of PDE1 inhibition and aid the further rational design of novel PDE1 inhibitors with higher affinities. Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.