Original articles
Fangyu Du, Ruolin Cao, Lu Chen, Jianwen Sun, Yajie Shi, Yang Fu, Bruce D. Hammock, Zhonghui Zheng, Zhongbo Liu, Guoliang Chen. Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1377-1389

Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain
Fangyu Dua, Ruolin Caoa, Lu Chena, Jianwen Suna, Yajie Shia, Yang Fua, Bruce D. Hammockb, Zhonghui Zhengc, Zhongbo Liud, Guoliang Chena
a. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China;
b. Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA;
c. Shandong Xinhua Pharmaceutical Co., Ltd., Zibo 255086, China;
d. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability in vitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor A20 also displayed robust analgesic effect in vivo and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (±)-EC-5026. In one word, the oral administration of A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain.
Key words:    Soluble epoxide hydrolase    Analgesia    Synthesis    Neuropathic pain    Inhibitor   
Received: 2021-07-10     Revised: 2021-09-08
DOI: 10.1016/j.apsb.2021.09.018
Funds: This work was funded by the Liaoning Revitalization Talents Program (XLYC1908031, China), Basic Research Project of Department of Education of Liaoning Province-natural sciences (2020LJC02, China), Major Basic Research Project of Natural Science Foundation of Shandong Province (ZR2018ZC1056, China), and partial support was provided by the NIH-NIEHS RIVER Award (R35 ES030443-01, USA), the NIEHS Superfund Research Program (P42 ES004699, USA).
Corresponding author: Zhongbo Liu,E-mai:546265581@qq.com;Guoliang Chen,E-mai:chenguoliang@syphu.edu.cn     Email:546265581@qq.com;chenguoliang@syphu.edu.cn
Author description:
PDF(KB) Free
Fangyu Du
Ruolin Cao
Lu Chen
Jianwen Sun
Yajie Shi
Yang Fu
Bruce D. Hammock
Zhonghui Zheng
Zhongbo Liu
Guoliang Chen

[1] Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008; 70: 1630-1635
[2] Bouhassira D. Neuropathic pain: definition, assessment and epidemiology. Rev Neurol (Paris) 2019; 175: 16-25
[3] van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 2014; 155: 654-662
[4] St John SE. Advances in understanding nociception and neuropathic pain. J Neurol 2018; 265: 231-238
[5] Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 2010; 9: 807-819
[6] Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology 2018; 129: 343-366
[7] Fiore NT, Austin PJ. Are the emergence of affective disturbances in neuropathic pain states contingent on supraspinal neuroinflammation?. Brain Behav Immun 2016; 56: 397-411
[8] Song J, Yu H, Liu Y. Current status of treatment and drug discovery for neuropathic pain. Acta Pharm Sin 2021; 56: 679-688
[9] Shinozaki T, Yamada T, Nonaka T, Yamamoto T. Acetaminophen and non-steroidal anti-inflammatory drugs interact with morphine and tramadol analgesia for the treatment of neuropathic pain in rats. J Anesth 2015; 29: 386-395
[10] Martinez-Navarro M, Maldonado R, Banos JE. Why mu-opioid agonists have less analgesic efficacy in neuropathic pain. Eur J Pain 2019; 23: 435-454
[11] Altiparmak B, Cil H, Celebi N. Effect of melatonin on the daytime sleepiness side-effect of gabapentin in adults patients with neuropathic pain. Rev Bras Anestesiol 2019; 69: 137-143
[12] Wagner K, Yang J, Inceoglu B, Hammock BD. Soluble epoxide hydrolase inhibition is antinociceptive in a mouse model of diabetic neuropathy. J Pain 2014; 15: 907-914
[13] Macone A, Otis JAD. Neuropathic pain. Semin Neurol 2018; 38: 644-653
[14] Gopalsamy B, Farouk AAO, Tengku Mohamad TAS, Sulaiman MR, Perimal EK. Antiallodynic and antihyperalgesic activities of zerumbone via the suppression of IL-1β, IL-6, and TNF-α in a mouse model of neuropathic pain. J Pain Res 2017; 10: 2605-2619
[15] Kaspera R, Totah RA. Epoxyeicosatrienoic acids: formation, metabolism and potential role in tissue physiology and pathology. Expet Opin Drug Metabol Toxicol 2009; 5: 757-771
[16] Wagner KM, Gomes A, Mcreynolds CB, Hammock BD. Soluble epoxide hydrolase regulation of lipid mediators limits pain. Neurotherapeutics 2020; 17: 900-916
[17] Morisseau C, Hammock BD. Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health. Annu Rev Pharmacol 2013; 53: 37-58
[18] Morin C, Sirois M, Echave V, Albadine R, Rousseau E. 17,18-Epoxyeicosatetraenoic acid targets PPARγ and p38 mitogen-activated protein kinase to mediate its anti-inflammatory effects in the lung: role of soluble epoxide hydrolase. Am J Resp Cell Mol 2010; 43: 564-575
[19] Wagner KM, McReynolds CB, Schmidt WK, Hammock BD. Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases. Pharmacol Ther 2017; 180: 62-76
[20] Wagner KM, Atone J, Hammock BD. Soluble epoxide hydrolase inhibitor mediated analgesia lacks tolerance in rat models. Brain Res 2020; 1728: 146573
[21] Hammock BD, McReynolds CB, Wagner K, Buckpitt A, Cortes-Puch I, Croston G, et al. Movement to the clinic of soluble epoxide hydrolase inhibitor EC5026 as an analgesic for neuropathic pain and for use as a nonaddictive opioid alternative. J Med Chem 2021; 64: 1856-1872
[22] Chiamvimonvat N, Ho CM, Tsai HJ, Hammock BD. The soluble epoxide hydrolase as a pharmaceutical target for hypertension. J Cardiovasc Pharmacol 2007; 50: 225-237
[23] Imig JD, Zhao X, Capdevila JH, Morisseau C, Hammock BD. Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension. Hypertension 2002; 39: 690-694
[24] Chen D, Whitcomb R, MacIntyre E, Tran V, Do ZN, Sabry J, et al. Pharmacokinetics and pharmacodynamics of AR9281, an inhibitor of soluble epoxide hydrolase, in single-and multiple-dose studies in healthy human subjects. J Clin Pharmacol. 2012; 52: 319-328
[25] Wang L, Yang J, Guo L, Uyeminami D, Dong H, Hammock BD, et al. Use of a soluble epoxide hydrolase inhibitor in smoke-induced chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2012; 46: 614-622
[26] Lazaar AL,Yang L, Boardley RL, Goyal NS, Robertson J, Baldwin SJ, et al. Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor. Br J Clin Pharmacol 2016; 81: 971-979
[27] Mao J, Gold MS, Backonja MM. Combination drug therapy for chronic pain: a call for more clinical studies. J Pain 2011; 12: 157-166
[28] Lee KSS, Ng JC, Yang J, Hwang SH, Morisseau C, Wagner K, et al. Preparation and evaluation of soluble epoxide hydrolase inhibitors with improved physical properties and potencies for treating diabetic neuropathic pain. Bioorg Med Chem 2020; 28: 115735
[29] Du F, Sun W, Morisseau C, Hammock BD, Bao X, Liu Q, et al. Discovery of memantinyl urea derivatives as potent soluble epoxide hydrolase inhibitors against lipopolysaccharide-induced sepsis. Eur J Med Chem 2021; 223: 113678
[30] Wolf NM, Morisseau C, Jones PD, Hock B, Hammock BD. Development of a high-throughput screen for soluble epoxide hydrolase inhibition. Anal Biochem 2006; 355: 71-80
[31] Leeson P, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov 2007; 6: 881-890
[32] Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55-63
[33] Guida F, De Gregorio D, Palazzo E, Ricciardi F, Boccella S, Belardo C, et al. Behavioral, biochemical and electrophysiological changes in spared nerve injury model of neuropathic pain. Int J Mol Sci 2020; 21: 3396
[34] Boccella S, Guida F, Palazzo E; Marabese I, de Novellis V, Maione S, et al. Spared nerve injury as a long-lasting model of neuropathic pain. Methods Mol Biol 2018; 1727: 373-378
[35] Jin X, Luo A, Zhang G. Comparison of the establishment and afficacy of three neuropathic pain models. J Clin Anesth 2005; 21: 338-340
Similar articles:
1.Chen Chen, Tianyu Zhu, Xiaoqin Liu, Dongrong Zhu, Yi Zhang, Sifang Wu, Chao Han, Hao Zhang, Jianguang Luo, Lingyi Kong.Identification of a novel PHGDH covalent inhibitor by chemical proteomics and phenotypic profiling[J]. Acta Pharmaceutica Sinica B, 2022,12(1): 246-261
2.Fanxun Zeng, Shiliang Li, Guantian Yang, Yating Luo, Tiantian Qi, Yingfan Liang, Tingyuan Yang, Letian Zhang, Rui Wang, Lili Zhu, Honglin Li, Xiaoyong Xu.Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis[J]. Acta Pharmaceutica Sinica B, 2021,11(3): 795-809
3.Yuxi Wang, Jian Gao, Song Zhao, Yan Song, Han Huang, Guiwang Zhu, Peili Jiao, Xiangqing Xu, Guisen Zhang, Kewei Wang, Liangren Zhang, Zhenming Liu.Discovery of 4-arylthiophene-3-carboxylic acid as inhibitor of ANO1 and its effect as analgesic agent[J]. Acta Pharmaceutica Sinica B, 2021,11(7): 1947-1964
4.Yuqin Yao, Zhuowei Liu, Manyu Zhao, Zhengxia Chen, Peng Li, Yang Zhang, Yuxi Wang, Chengjian Zhao, Chaofeng Long, Xiaoxin Chen, Jinliang Yang.Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy[J]. Acta Pharmaceutica Sinica B, 2020,10(8): 1453-1475
5.Biao Wang, Fu Peng, Wei Huang, Jin Zhou, Nan Zhang, Jia Sheng, Phensinee Haruehanroengra, Gu He, Bo Han.Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma[J]. Acta Pharmaceutica Sinica B, 2020,10(8): 1492-1510
6.Ryuji Uchida, Mio Kawaguchi, Noriko Sato, Hiroshi Tomoda.Stereochemistries of monapinones produced by Talaromyces pinophilus FKI-3864[J]. Acta Pharmaceutica Sinica B, 2013,3(3): 163-166
7.Dongying Wu, Kaiyiu Ting, Yaokai Duan, Na Lia, Jianguo Li, Liangren Zhang, Honcheung Lee, Lihe Zhang.Synthesis and activity of novel indole derivatives as inhibitors of CD38[J]. Acta Pharmaceutica Sinica B, 2013,3(4): 245-253
Similar articles: