Phosphodiesterase 10 (PDE10) inhibitors have received much attention as promising therapeutic agents for central nervous system (CNS) disorders such as schizophrenia and Huntington's disease. Recently, a hit compound 1 with a novel chromone scaffold has showed moderate inhibitory activity against PDE10A (IC50 = 500 nM). Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC50 of 6.5 nM), remarkable selectivity (> 95-fold over other PDEs), and good metabolic stability (RLM t1/2 = 105 min) by using an integrated strategy (molecular modeling, chemical synthesis, bioassay, and cocrystal structure). The cocrystal structural information provides insights into the binding pattern of 3e in the PDE10A catalytic domain to highlight the key role of the halogen and hydrogen bonds toward Tyr524 and Tyr693, respectively, thereby resulting in high selectivity against other PDEs. These new observations are of benefit for the rational design of the next generation PDE10 inhibitors for CNS disorders.

中文翻译：

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发现和优化作为新型选择性磷酸二酯酶10抑制剂的色酮衍生物。

磷酸二酯酶10（PDE10）抑制剂作为中枢神经系统（CNS）疾病（如精神分裂症和亨廷顿氏病）的有前途的治疗剂受到了广泛关注。最近，具有新型色酮支架的命中化合物1对PDE10A表现出中等抑制作用（IC50 = 500 nM）。领先的优化方法使化合物3e的抑制活性提高（IC50为6.5 nM），选择性显着（比其他PDE高95倍），并具有良好的代谢稳定性（RLM t1 / 2 = 105分钟）集成策略（分子建模，化学合成，生物测定和共晶结构）。共晶结构信息提供了有关PDE10A催化域中3e结合模式的见解，以突出卤素和氢键对Tyr524和Tyr693的关键作用，分别导致对其他PDE的高选择性。这些新的观察结果对于合理设计用于中枢神经系统疾病的下一代PDE10抑制剂是有益的。