SAR study on Novel truxillic acid monoester-Based inhibitors of fatty acid binding proteins as Next-Generation antinociceptive agents.
SAR study on Novel truxillic acid monoester-Based inhibitors of fatty acid binding proteins as Next-Generation antinociceptive agents.
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作为下一代抗伤害药的新型特鲁西酸单酯脂肪酸结合蛋白抑制剂的 SAR 研究。
DOI：
10.1016/j.bioorg.2022.106184
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发表时间：
2022
影响因子：
5.1
通讯作者：
Ojima,Iwao
中科院分区：
文献类型：
--
作者：
Wang,Hehe;Taouil,Adam;Awwa,Monaf;Clement,Timothy;Zhu,Chuanzhou;Kim,Jinwoo;Rendina,Dominick;Jayanetti,Kalani;Maharaj,Atri;Wang,Liqun;Bogdan,Diane;Pepe,Antonella;Kaczocha,Martin;Ojima,Iwao
Fatty acid binding protein 5 (FABP5) is a highly promising target for the development of analgesics as its inhibition is devoid of CB1R-dependent side-effects. The design and discovery of highly potent and FABP5-selective truxillic acid (TA) monoesters (TAMEs) is the primary aim of the present study. On the basis of molecular docking analysis, ca. 2,000 TAMEs were designed and screenedin silico, to funnel down to 55 new TAMEs, which were synthesized and assayed for their affinity (Ki) to FABP5, 3 and 7. The SAR study revealed that the introduction of H-bond acceptors to the far end of the 1,1′-biphenyl-3-yl and 1,1′-biphenyl-2-yl ester moieties improved the affinity of α-TAMEs to FABP5. Compound γ-3is the first γ-TAME, demonstrating a high affinity to FABP5 and competing with α-TAMEs. We identified the best 20 TAMEs based on the FABP5/3 selectivity index. The clear front runner isα-16, bearing a 2‑indanyl ester moiety. In sharp contrast, no ε-TAMEs made the top 20 in this list. However,α-19andε-202, have been identified as potent FABP3-selective inhibitors for applications related to their possible use in the protection of cardiac myocytes and the reduction of α-synuclein accumulation in Parkinson’s disease. Among the best 20 TAMEs selected based on the affinity to FABP7, 13 out of 20 TAMEs were found to be FABP7-selective, withα-21as the most selective. This study identified several TAMEs as FABP7-selective inhibitors, which would have potentially beneficial therapeutic effects in diseases such as Down’s syndrome, schizophrenia, breast cancer, and astrocytoma. We successfully introduced the α-TA monosilyl ester (TAMSE)-mediated protocol to dramatically improve the overall yields of α-TAMEs. α-TAMSEs with TBDPS as the silyl group is isolated in good yields and unreacted α-TA/ α-MeO-TA, as well as disilyl esters (α-TADSEs) are fully recycled. Molecular docking analysis provided rational explanations for the observed binding affinity and selectivity of the FABP3, 5 and 7 inhibitors, including their α, γ and ε isomers, in this study.
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影响因子：
2.9
作者：
Hsu HC;Tong S;Zhou Y;Elmes MW;Yan S;Kaczocha M;Deutsch DG;Rizzo RC;Ojima I;Li H
通讯作者：
Li H
环丁烷-1,3-二羧酸的电解氧化。
DOI：
--
发表时间：
1966
期刊：
影响因子：
--
作者：
A. F. Vellturo;G. Griffin
通讯作者：
G. Griffin
DOI：
--
发表时间：
1998-11
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Mario D. Aceto;S. Scates;R. Razdan;Billy R. Martin
通讯作者：
Mario D. Aceto;S. Scates;R. Razdan;Billy R. Martin
天然存在的和相关的合成大麻素及其潜在的治疗应用。
DOI：
10.2174/157488909788453031
发表时间：
2009
期刊：
Recent patents on CNS drug discovery
影响因子：
--
作者：
Galal,AhmedM;Slade,Desmond;Gul,Waseem;El-Alfy,AbirT;Ferreira,Daneel;Elsohly,MahmoudA
通讯作者：
Elsohly,MahmoudA
影响因子：
6.7
作者：
Yan S;Elmes MW;Tong S;Hu K;Awwa M;Teng GYH;Jing Y;Freitag M;Gan Q;Clement T;Wei L;Sweeney JM;Joseph OM;Che J;Carbonetti GS;Wang L;Bogdan DM;Falcone J;Smietalo N;Zhou Y;Ralph B;Hsu HC;Li H;Rizzo RC;Deutsch DG;Kaczocha M;Ojima I
通讯作者：
Ojima I