Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors
Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors
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作为新型选择性磷酸二酯酶 10 抑制剂的色酮衍生物的发现和优化
DOI：
10.1021/acschemneuro.0c00024
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发表时间：
2020-04-01
影响因子：
5
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
--
作者：
Yu, Yan-Fa;Zhang, Chen;Luo, Hai-Bin
磷酸二酯酶10(PDE10)抑制剂作为治疗精神分裂症和亨廷顿病等中枢神经系统(CNS)疾病的有前景的药物而受到广泛关注。最近，一种带有新型色酮支架的HIT化合物1对PDE10A显示出中等的抑制活性(IC50=500 nM)。通过采用综合策略(分子模拟、化学合成、生物测定和共晶体结构)，Hit-to-Lead优化得到了具有更好的抑制活性(IC50=6.5 nM)、显著的选择性(是其他PDE的95倍)和良好的代谢稳定性(RLm t(1/2)=105min)的化合物3E。共晶结构信息提供了对PDE10A催化结构域中3E的结合模式的见解，以突出卤素和氢键分别对Tyr524和Tyr693的关键作用，从而导致对其他PDE的高选择性。这些新的观察结果有助于合理设计治疗中枢神经系统疾病的下一代PDE10抑制剂。
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 shown moderate inhibitory activity against PDE10A (IC50 = 500 nM). Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC50 = 6.5 nM), remarkable selectivity (>95-fold over other PDEs), and good metabolic stability (RLM t(1/2) = 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.