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发现一系列大环化合物作为有效的 抑制剂。

Discovery of a Series of Macrocycles as Potent Inhibitors of .

机构信息

Department of Chemistry - BMC, Uppsala University, 751 23 Uppsala, Sweden.

Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, 751 24 Uppsala, Sweden.

出版信息

J Med Chem. 2024 Oct 24;67(20):18170-18193. doi: 10.1021/acs.jmedchem.4c01370. Epub 2024 Oct 8.

DOI:10.1021/acs.jmedchem.4c01370
PMID:39378318
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11513892/
Abstract

Macrocycles are prominent among drugs for treatment of infectious disease, with many originating from natural products. Herein we report on the discovery of a series of macrocycles structurally related to the natural product hymenocardine. Members of this series were found to inhibit the growth of , the parasite responsible for most malaria cases, and of four kinetoplastid parasites. Notably, macrocycles more potent than miltefosine, the only oral drug used for the treatment of the neglected tropical disease visceral leishmaniasis, were identified in a phenotypic screen of . profiling highlighted that potent inhibitors had satisfactory cell permeability with a low efflux ratio, indicating their potential for oral administration, but low solubility and metabolic stability. Analysis of predicted crystal structures suggests that optimization should focus on the reduction of π-π crystal packing interactions to reduce the strong crystalline interactions and improve the solubility of the most potent lead.

摘要

大环化合物是治疗传染病的药物中的佼佼者，其中许多源自天然产物。在此，我们报告了一系列与天然产物海曼卡霉素结构相关的大环化合物的发现。该系列化合物被发现能抑制寄生虫生长，而寄生虫是引起大多数疟疾病例的罪魁祸首，还能抑制四种动基体原生动物寄生虫的生长。值得注意的是，在针对的表型筛选中发现了比米替福新更有效的大环化合物，米替福新是唯一用于治疗被忽视的热带病内脏利什曼病的口服药物。药物特征分析突出表明，具有高细胞通透性和低外排比的有效抑制剂表明它们具有口服给药的潜力，但溶解度和代谢稳定性较低。预测晶体结构的分析表明，优化应侧重于减少π-π晶体堆积相互作用，以降低强烈的晶体相互作用并提高最有效先导化合物的溶解度。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/9b306dd72c83/jm4c01370_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/27dec8e584b4/jm4c01370_0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/03b1e6384315/jm4c01370_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/ebe1d59a1480/jm4c01370_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/19890ba7f6f7/jm4c01370_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/7454f274be6f/jm4c01370_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/e9e48ead15be/jm4c01370_0010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/9f4232c6d397/jm4c01370_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/9b306dd72c83/jm4c01370_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/27dec8e584b4/jm4c01370_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/4e2d970cb5bd/jm4c01370_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/5adc0da449dc/jm4c01370_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/96cfe43a0bec/jm4c01370_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/03b1e6384315/jm4c01370_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/ebe1d59a1480/jm4c01370_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/19890ba7f6f7/jm4c01370_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/7454f274be6f/jm4c01370_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/e9e48ead15be/jm4c01370_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/4cfe4ac31f5f/jm4c01370_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/9f4232c6d397/jm4c01370_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ea9/11513892/9b306dd72c83/jm4c01370_0008.jpg

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1
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Nature. 2024 May;629(8013):919-926. doi: 10.1038/s41586-024-07205-6. Epub 2024 Apr 8.
2
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Nat Commun. 2024 Mar 21;15(1):2534. doi: 10.1038/s41467-024-46721-x.
3
Molecular chameleons in drug discovery.药物发现中的分子变色龙。
Nat Rev Chem. 2024 Jan;8(1):45-60. doi: 10.1038/s41570-023-00563-1. Epub 2023 Dec 20.
4
Free Energy Perturbation Approach for Accurate Crystalline Aqueous Solubility Predictions.用于精确预测晶体水溶解度的自由能微扰方法。
J Med Chem. 2023 Dec 14;66(23):15883-15893. doi: 10.1021/acs.jmedchem.3c01339. Epub 2023 Nov 28.
5
Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.验证一种针对细胞内难成药靶标的超越 Rule of 5 的新型口服药物研发方法。
J Am Chem Soc. 2023 Nov 8;145(44):24035-24051. doi: 10.1021/jacs.3c07145. Epub 2023 Oct 24.
6
Structure-Property Optimization of a Series of Imidazopyridines for Visceral Leishmaniasis.一系列用于内脏利什曼病的咪唑并吡啶的结构-性质优化。
ACS Infect Dis. 2023 Aug 11;9(8):1470-1487. doi: 10.1021/acsinfecdis.3c00040. Epub 2023 Jul 7.
7
Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.口服生物利用的大环肽，抑制 PCSK9 与低密度脂蛋白受体的结合。
Circulation. 2023 Jul 11;148(2):144-158. doi: 10.1161/CIRCULATIONAHA.122.063372. Epub 2023 May 1.
8
Macrocycles in Drug Discovery─Learning from the Past for the Future.药物发现中的大环化合物——从过去中学习，为未来而创新。
J Med Chem. 2023 Apr 27;66(8):5377-5396. doi: 10.1021/acs.jmedchem.3c00134. Epub 2023 Apr 5.
9
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10
Trends in oral small-molecule drug discovery and product development based on product launches before and after the Rule of Five.基于“五规则”前后产品上市情况的口服小分子药物发现与产品开发趋势
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