Development of multitarget inhibitors for the treatment of pain: Design, synthesis, biological evaluation and molecular modeling studies.
Development of multitarget inhibitors for the treatment of pain: Design, synthesis, biological evaluation and molecular modeling studies.
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DOI：
10.1016/j.bioorg.2020.104165
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发表时间：
2020-10
影响因子：
5.1
通讯作者：
Pecic S
中科院分区：
文献类型：
--
作者：
Wilt S;Kodani S;Le TNH;Nguyen L;Vo N;Ly T;Rodriguez M;Hudson PK;Morisseau C;Hammock BD;Pecic S
多靶向配体是一类很有前途的药物，可用于发现治疗难治性疾病的创新疗法。在这项研究中，我们设计了针对人脂肪酸酰胺水解酶(FAAH)和人可溶性环氧化物水解酶(SEH)的双重抑制剂。同时靶向这两种酶和单一靶点抑制剂可以协同减少炎症和神经病理性疼痛；因此，双重FAAH/sEH抑制剂可能是有效的止痛药。在这里，我们确定了哌啶基磺酰胺部分是一种常见的药效团，并对几种抑制剂进行了优化，使其同时对两种目标酶具有良好的抑制作用。此外，几种抑制剂显示出良好的预测药代动力学特性。这些结果表明，这一系列的抑制剂有潜力被进一步开发为新的领先候选药物和疼痛治疗药物。
Multitarget-directed ligands are a promising class of drugs for discovering innovative new therapies for difficult to treat diseases. In this study, we designed dual inhibitors targeting the human fatty acid amide hydrolase (FAAH) enzyme and human soluble epoxide hydrolase (sEH) enzyme. Targeting both of these enzymes concurrently with single target inhibitors synergistically reduces inflammatory and neuropathic pain; thus, dual FAAH/sEH inhibitors are likely to be powerful analgesics. Here, we identified the piperidinyl-sulfonamide moiety as a common pharmacophore and optimized several inhibitors to have excellent inhibition profiles on both targeted enzymes simultaneously. In addition, several inhibitors show good predicted pharmacokinetic properties. These results suggest that this series of inhibitors has the potential to be further developed as new lead candidates and therapeutics in pain management.
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影响因子：
2.9
作者：
Ostermann AI;Herbers J;Willenberg I;Chen R;Hwang SH;Greite R;Morisseau C;Gueler F;Hammock BD;Schebb NH
通讯作者：
Schebb NH
影响因子：
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影响因子：
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