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基于 SLC10 载体 ASBT、NTCP 和 SOAT 上 S1647 的苯磺酰胺基苯甲酰胺抑制剂的结构-活性关系和靶标选择性。

Structure-Activity Relationships and Target Selectivity of Phenylsulfonylamino-Benzanilide Inhibitors Based on S1647 at the SLC10 Carriers ASBT, NTCP, and SOAT.

机构信息

Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Biomedical Research Center Seltersberg (BFS), Justus Liebig University of Giessen, Schubertstr. 81, Giessen 35392, Germany.

Department of Medicinal Chemistry and Core Facility Medicinal Chemistry, Center for Tumor- and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, Marburg 35043, Germany.

出版信息

J Med Chem. 2024 Nov 14;67(21):19342-19364. doi: 10.1021/acs.jmedchem.4c01743. Epub 2024 Oct 17.

DOI:10.1021/acs.jmedchem.4c01743
PMID:39419503
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11571210/
Abstract

The intestinal bile acid carrier ASBT (), the hepatic bile acid carrier NTCP (), and the steroid sulfate carrier SOAT (), all members of the solute carrier family SLC10, are established drug targets. The ASBT inhibitors odevixibat, maralixibat, and elobixibat are used to treat intrahepatic cholestasis, cholestatic pruritus, and obstipation. The peptide drug bulevirtide blocks binding of the hepatitis B and D viruses to NTCP and thereby inhibits the virus's entry into hepatocytes. Experimental SOAT inhibitors have antiproliferative effects on hormone-dependent breast cancer cells. The phenylsulfonylamino-benzanilide S1647 is an inhibitor of ASBT and SOAT. The present study aimed to comparatively analyze a set of newly synthesized and commercially available S1647 derivatives for their transport inhibition against ASBT, NTCP, and SOAT. Structure-activity relationships were systematically analyzed regarding potency and target specificity to elucidate whether this compound class is worth being further developed in preclinical studies for pharmacological ASBT, NTCP, and/or SOAT inhibition.

摘要

肠道胆汁酸载体 ASBT（）、肝胆汁酸载体 NTCP（）和甾体硫酸酯载体 SOAT（）均属于溶质载体家族 SLC10，是已确立的药物靶点。ASBT 抑制剂奥贝胆酸、马洛胆酸和利昔胆酸用于治疗原发性胆汁性胆管炎、胆汁淤积性瘙痒和便秘。肽类药物布瓦西坦通过阻断乙型肝炎和丁型肝炎病毒与 NTCP 的结合，从而抑制病毒进入肝细胞。实验性 SOAT 抑制剂对激素依赖性乳腺癌细胞具有抗增殖作用。苯磺酰胺基苯甲酰胺 S1647 是 ASBT 和 SOAT 的抑制剂。本研究旨在比较分析一组新合成的和市售的 S1647 衍生物对 ASBT、NTCP 和 SOAT 的转运抑制作用。系统分析了构效关系，包括效力和靶标特异性，以阐明该化合物类是否值得在临床前研究中进一步开发用于药理学 ASBT、NTCP 和/或 SOAT 抑制。

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本文引用的文献

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Targeting bile salt homeostasis in biliary diseases.靶向胆汁盐动态平衡治疗胆汁淤积性疾病
Curr Opin Gastroenterol. 2024 Mar 1;40(2):62-69. doi: 10.1097/MOG.0000000000000997. Epub 2024 Jan 10.
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Role of sodium taurocholate cotransporting polypeptide (NTCP) in HBV-induced hepatitis: Opportunities for developing novel therapeutics.牛磺胆酸钠共转运多肽（NTCP）在乙型肝炎病毒诱导的肝炎中的作用：开发新型治疗方法的机会。
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Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis.
抑制肾顶端钠依赖性胆汁酸转运体可预防梗阻性胆汁淤积小鼠的胆血症性肾病。
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Role of the Sodium-Dependent Organic Anion Transporter (SOAT/SLC10A6) in Physiology and Pathophysiology.钠离子依赖型有机阴离子转运体（SOAT/SLC10A6）在生理学和病理生理学中的作用。
Int J Mol Sci. 2023 Jun 8;24(12):9926. doi: 10.3390/ijms24129926.
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Interactions of Na/taurocholate cotransporting polypeptide with host cellular proteins upon hepatitis B and D virus infection: novel potential targets for antiviral therapy.乙型肝炎和丁型肝炎病毒感染时牛磺胆酸钠共转运多肽与宿主细胞蛋白的相互作用：抗病毒治疗的新潜在靶点。
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Discovery and development of benzene sulfonamide derivatives as anti-hepatic fibrosis agents.苯磺酰胺衍生物的发现与开发：抗肝纤维化药物。
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A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans.A3907，一种全身性 ASBT 抑制剂，通过多器官作用改善了小鼠的胆汁淤积，并显示出对人类的转化相关性。
Hepatology. 2023 Sep 1;78(3):709-726. doi: 10.1097/HEP.0000000000000376. Epub 2023 Apr 1.
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Systemic ASBT inactivation protects against liver damage in obstructive cholestasis in mice.全身性ASBT失活可保护小鼠阻塞性胆汁淤积中的肝脏免受损伤。
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Targeting bile acid signaling for the treatment of liver diseases: From bench to bed.针对胆汁酸信号通路治疗肝脏疾病：从实验室到临床。
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