Discovery of Potent and Selective Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1

We disclose the discovery and X-ray cocrystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor (S)-3 readily attains free plasma concentrations above PDE1 IC50 values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue. These compounds represent promising new tools to probe the value of PDE1 inhibition in the treatment of cardiovascular disease.本研究公开了一类强效、选择性磷酸二酯酶1（PDE1）喹唑啉类抑制剂的发现及其X射线共晶数据。抑制剂(S)-3的游离血浆浓度可轻易达到高于PDE1半最大抑制浓度（IC50）的水平，且脑组织摄取受限。外消旋化合物3可在人心肌组织的可溶性样本中抑制超过75%的PDE水解活性，这与该组织中PDE1活性升高的现象一致。上述化合物为探究PDE1抑制在心血管疾病治疗中的应用价值提供了极具潜力的新型研究工具。