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设计、合成及一种强力可溶性环氧化物水解酶抑制剂的药理学特征，用于治疗急性胰腺炎。

Design, Synthesis, and Pharmacological Characterization of a Potent Soluble Epoxide Hydrolase Inhibitor for the Treatment of Acute Pancreatitis.

机构信息

Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084 Fisciano, Salerno, Italy.

Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49, 80131 Naples, Italy.

出版信息

J Med Chem. 2023 Jul 13;66(13):9201-9222. doi: 10.1021/acs.jmedchem.3c00831. Epub 2023 Jun 19.

DOI:10.1021/acs.jmedchem.3c00831
PMID:37334504
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10350924/
Abstract

Acute pancreatitis (AP) is a potentially life-threatening illness characterized by an exacerbated inflammatory response with limited options for pharmacological treatment. Here, we describe the rational development of a library of soluble epoxide hydrolase (sEH) inhibitors for the treatment of AP. Synthesized compounds were screened for their sEH inhibitory potency and selectivity, and the results were rationalized by means of molecular modeling studies. The most potent compounds were studied for their pharmacokinetic profile, where compound emerged as a promising lead. In fact, compound demonstrated a remarkable efficacy in reducing the inflammatory damage in cerulein-induced AP in mice. Targeted metabololipidomic analysis further substantiated sEH inhibition as a molecular mechanism of the compound underlying anti-AP activity . Finally, pharmacokinetic assessment demonstrated a suitable profile of . Collectively, compound displays strong effectiveness as sEH inhibitor with potential for pharmacological AP treatment.

摘要

急性胰腺炎（AP）是一种潜在的危及生命的疾病，其特征是炎症反应加剧，而药物治疗的选择有限。在这里，我们描述了一个可溶性环氧化物水解酶（sEH）抑制剂文库的合理开发，用于治疗 AP。合成的化合物被筛选出其 sEH 抑制活性和选择性，结果通过分子建模研究进行了合理化。对最有效的化合物进行了药代动力学研究，其中化合物脱颖而出成为有前途的先导化合物。事实上，化合物在降低小鼠中胰酶诱导的 AP 的炎症损伤方面表现出显著的疗效。靶向代谢脂质组学分析进一步证实 sEH 抑制是该化合物发挥抗 AP 活性的分子机制。最后，药代动力学评估显示了 的合适特征。总之，化合物作为 sEH 抑制剂具有很强的效果，具有治疗急性胰腺炎的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/278d465ff69e/jm3c00831_0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/fbccb32ea87e/jm3c00831_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/0e01fe8040a5/jm3c00831_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/e8dec72ec303/jm3c00831_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/278d465ff69e/jm3c00831_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/2c4ca2706c0d/jm3c00831_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/2e5ba528bdd0/jm3c00831_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/d9c1684dedfb/jm3c00831_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/10ebcf73067a/jm3c00831_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/68f1b0d22681/jm3c00831_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/980b02f83e1b/jm3c00831_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/5a5101237471/jm3c00831_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/fbccb32ea87e/jm3c00831_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/0e01fe8040a5/jm3c00831_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/e8dec72ec303/jm3c00831_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cfe/10350924/278d465ff69e/jm3c00831_0009.jpg

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