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.

本研究公开了强效、选择性磷酸二酯酶1（PDE1）喹唑啉类抑制剂的发现过程及X射线共晶数据。抑制剂(S)-3可轻松达到高于PDE1半数抑制浓度（IC50）的游离血浆浓度，且血脑屏障穿透能力受限。外消旋体化合物3可在人心肌可溶性样本中抑制超过75%的PDE水解活性，与该组织中PDE1活性升高的现象相符。此类化合物为探究PDE1抑制疗法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。