Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia.
Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia.
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通过与 PDE8 H-pocket 的独特相互作用，基于结构发现口服有效抑制剂，用于治疗血管性痴呆
DOI：
10.1016/j.apsb.2022.02.012
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发表时间：
2022-07
影响因子：
14.5
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
--
作者：
Wu, Xu-Nian;Zhou, Qian;Huang, Ya-Dan;Xie, Xi;Li, Zhe;Wu, Yinuo;Luo, Hai-Bin
关键词：
我们以前的研究表明，磷酸二酯酶8（PDE 8）可以作为一个潜在的目标，血管性痴呆（VaD）使用化学探针3a。然而，化合物3a是一种手性化合物，在HPLC上通过手性拆分得到，限制了其在临床上的应用。本文中，发现了一系列非手性9-苄基-2-氯-腺嘌呤衍生物作为新型PDE 8抑制剂。铅15对PDE 8A具有很强的抑制活性（IC 50 = 11 nmol/L），对其他PDE具有很高的选择性，并具有显著的药物样活性（值得一提的是其生物利用度高达100%）。15的口服给药显著改善了右脑的cAMP水平，并在VaD小鼠模型中表现出对认知改善的剂量依赖性作用。值得注意的是，PDE 8A-15复合物的X射线晶体结构表明，15的强亲和力和高选择性可能来自与H-口袋的独特相互作用，包括与Phe 785的T形π-π相互作用以及独特的H-键网络，这在其他PDE-抑制剂复合物中从未观察到过。为进一步合理设计新型PDE 8选择性抑制剂提供了新的策略。基于结构优化的3a通过与H-口袋的独特相互作用产生非手性、口服活性和选择性的PDE 8抑制剂15，其在VaD小鼠中表现出显著的记忆改善作用。
Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A–15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π–π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE−inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8. Structure-based optimization of 3a resulted in a non-chiral, orally active, and selective PDE8 inhibitor 15via unique interactions with H-pocket, which exhibited remarkable memory improvement effects in VaD mice.
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影响因子：
12.7
作者：
Kalaria RN
通讯作者：
Kalaria RN
影响因子：
5.7
作者：
Card, GL;England, BP;Zhang, KYJ
通讯作者：
Zhang, KYJ
影响因子：
4.8
作者：
Gamanuma, M;Yuasa, K;Omori, K
通讯作者：
Omori, K
DOI：
10.1073/pnas.95.15.8991
发表时间：
1998-07-21
影响因子：
11.1
作者：
Soderling, SH;Bayuga, SJ;Beavo, JA
通讯作者：
Beavo, JA
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG