新型 N-杂环-1-苄基-1H-苯并[d]咪唑-2-胺的设计、合成与表征作为选择性 TRPC5 抑制剂，导致选择性化合物 AC1903 的鉴定。
Design, synthesis and characterization of novel N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors leading to the identification of the selective compound, AC1903.
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, United States; Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States.
出版信息
Bioorg Med Chem Lett. 2019 Jan 15;29(2):155-159. doi: 10.1016/j.bmcl.2018.12.007. Epub 2018 Dec 4.
Abstract
The transient receptor potential cation channel 5 (TRPC5) has been previously shown to affect podocyte survival in the kidney. As such, inhibitors of TRPC5 are interesting candidates for the treatment of chronic kidney disease (CKD). Herein, we report the synthesis and biological characterization of a series of N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors. Work reported here evaluates the benzimidazole scaffold and substituents resulting in the discovery of AC1903, a TRPC5 inhibitor that is active in multiple animal models of CKD.
摘要
瞬时受体电位阳离子通道 5（TRPC5）先前已被证明会影响肾脏中的足细胞存活。因此，TRPC5 的抑制剂是治疗慢性肾病（CKD）的有前途的候选药物。在此，我们报告了一系列 N-杂环-1-苄基-1H-苯并[d]咪唑-2-胺作为选择性 TRPC5 抑制剂的合成和生物学特性。这里报道的工作评估了苯并咪唑骨架和取代基，从而发现了 AC1903，这是一种在多种 CKD 动物模型中都具有活性的 TRPC5 抑制剂。
相似文献
1
Design, synthesis and characterization of novel N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors leading to the identification of the selective compound, AC1903.新型 N-杂环-1-苄基-1H-苯并[d]咪唑-2-胺的设计、合成与表征作为选择性 TRPC5 抑制剂，导致选择性化合物 AC1903 的鉴定。
Bioorg Med Chem Lett. 2019 Jan 15;29(2):155-159. doi: 10.1016/j.bmcl.2018.12.007. Epub 2018 Dec 4.
2
Synthesis of AC1903 analogs as potent transient receptor potential canonical channel 4/5 inhibitors and biological evaluation.合成 AC1903 类似物作为有效的瞬时受体电位经典通道 4/5 抑制剂及生物学评价。
Bioorg Med Chem. 2022 Aug 15;68:116853. doi: 10.1016/j.bmc.2022.116853. Epub 2022 May 27.
3
Further Exploration of the Benzimidazole Scaffold as TRPC5 Inhibitors: Identification of 1-Alkyl-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazoles as Potent and Selective Inhibitors.进一步探索苯并咪唑支架作为 TRPC5 抑制剂：鉴定 1-烷基-2-(吡咯烷-1-基)-1H-苯并[d]咪唑作为有效和选择性抑制剂。
ChemMedChem. 2022 Jul 19;17(14):e202200151. doi: 10.1002/cmdc.202200151. Epub 2022 May 24.
4
Discovery of pyridazinone derivatives bearing tetrahydroimidazo[1,2-a]pyrazine scaffold as potent inhibitors of transient receptor potential canonical 5 to ameliorate hypertension-induced renal injury in rats.发现含有四氢咪唑并[1,2-a]吡嗪骨架的哒嗪酮衍生物是有效的瞬时受体电位经典型 5 抑制剂，可改善高血压大鼠肾损伤。
Eur J Med Chem. 2024 Sep 5;275:116565. doi: 10.1016/j.ejmech.2024.116565. Epub 2024 Jun 4.
5
A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models.TRPC5离子通道的小分子抑制剂可抑制动物模型中的进行性肾病。
Science. 2017 Dec 8;358(6368):1332-1336. doi: 10.1126/science.aal4178.
6
Nonselective TRPC channel inhibition and suppression of aminoglycoside-induced premature termination codon readthrough by the small molecule AC1903.非选择性 TRPC 通道抑制和小分子 AC1903 抑制氨基糖苷类诱导的过早终止密码子通读。
J Biol Chem. 2022 Feb;298(2):101546. doi: 10.1016/j.jbc.2021.101546. Epub 2022 Jan 6.
7
Discovery of pyrroledione analogs as potent transient receptor potential canonical channel 5 inhibitors.发现吡咯二酮类似物作为有效的瞬时受体电位经典通道 5 抑制剂。
Bioorg Med Chem Lett. 2022 Apr 1;61:128612. doi: 10.1016/j.bmcl.2022.128612. Epub 2022 Feb 7.
8
Novel Benzo[d]imidazole-based Heterocycles as Broad Spectrum Anti-viral Agents: Design, Synthesis and Exploration of Molecular Basis of Action.基于苯并[d]咪唑的新型杂环化合物作为广谱抗病毒剂：作用分子基础的设计、合成与探索
Mini Rev Med Chem. 2016;16(1):67-83. doi: 10.2174/138955751601151029115533.
9
Scaffold oriented synthesis. Part 4: design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing heterocycle forming and multicomponent reactions.导向支架合成。第 4 部分：新型 5-取代吲哚的设计、合成和生物评价作为有效的和选择性的激酶抑制剂，采用杂环形成和多组分反应。
Bioorg Med Chem Lett. 2011 Mar 1;21(5):1480-3. doi: 10.1016/j.bmcl.2011.01.001. Epub 2011 Jan 11.
10
Structural basis for human TRPC5 channel inhibition by two distinct inhibitors.人类 TRPC5 通道受两种不同抑制剂抑制的结构基础。
Elife. 2021 Mar 8;10:e63429. doi: 10.7554/eLife.63429.
引用本文的文献
1
Targeting TRPC-5 Channel Inhibition to Improve Penile Vascular Function in Erectile Dysfunction.靶向瞬时受体电位通道5（TRPC-5）抑制以改善勃起功能障碍中的阴茎血管功能。
Int J Mol Sci. 2025 Feb 8;26(4):1431. doi: 10.3390/ijms26041431.
2
A mild and scalable one-pot synthesis of N-substituted 2-aminobenzimidazoles via visible light mediated cyclodesulfurization.通过可见光介导的环脱硫反应温和且可扩展地一锅合成N-取代的2-氨基苯并咪唑。
Sci Rep. 2025 Feb 3;15(1):4096. doi: 10.1038/s41598-025-86772-8.
3
Synthesis of N-, O-, and S-heterocycles from aryl/alkyl alkynyl aldehydes.由芳基/烷基炔基醛合成氮杂环、氧杂环和硫杂环。
RSC Adv. 2023 May 9;13(20):13947-13970. doi: 10.1039/d3ra01778h. eCollection 2023 May 2.
4
Further Exploration of the Benzimidazole Scaffold as TRPC5 Inhibitors: Identification of 1-Alkyl-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazoles as Potent and Selective Inhibitors.进一步探索苯并咪唑支架作为 TRPC5 抑制剂：鉴定 1-烷基-2-(吡咯烷-1-基)-1H-苯并[d]咪唑作为有效和选择性抑制剂。
ChemMedChem. 2022 Jul 19;17(14):e202200151. doi: 10.1002/cmdc.202200151. Epub 2022 May 24.
5
Nonselective TRPC channel inhibition and suppression of aminoglycoside-induced premature termination codon readthrough by the small molecule AC1903.非选择性 TRPC 通道抑制和小分子 AC1903 抑制氨基糖苷类诱导的过早终止密码子通读。
J Biol Chem. 2022 Feb;298(2):101546. doi: 10.1016/j.jbc.2021.101546. Epub 2022 Jan 6.
6
Canonical transient receptor potential channels and their modulators: biology, pharmacology and therapeutic potentials.经典瞬时受体电位通道及其调节剂：生物学、药理学和治疗潜力。
Arch Pharm Res. 2021 Apr;44(4):354-377. doi: 10.1007/s12272-021-01319-5. Epub 2021 Mar 24.
7
[Correlation between transient receptor potential canonical channel with heart and kidney injure of rat model of obstructive sleep apnea hypopnea syndrome].[瞬时感受器电位香草酸亚型通道与阻塞性睡眠呼吸暂停低通气综合征大鼠模型心肾损伤的相关性]
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020 Aug 25;49(4):439-446. doi: 10.3785/j.issn.1008-9292.2020.04.16.
8
Canonical Transient Receptor Potential (TRPC) Channels in Nociception and Pathological Pain.规范瞬时受体电位（TRPC）通道在伤害感受和病理性疼痛中的作用。
Neural Plast. 2020 Mar 21;2020:3764193. doi: 10.1155/2020/3764193. eCollection 2020.
9
Discovery of a Potent and Selective TRPC5 Inhibitor, Efficacious in a Focal Segmental Glomerulosclerosis Model.发现一种强效且选择性的TRPC5抑制剂，在局灶节段性肾小球硬化模型中具有疗效。
ACS Med Chem Lett. 2019 Oct 22;10(11):1579-1585. doi: 10.1021/acsmedchemlett.9b00430. eCollection 2019 Nov 14.
10
Charting a TRP to Novel Therapeutic Destinations for Kidney Diseases.绘制 TRP 通往肾脏疾病新型治疗靶点的路线图。
Trends Pharmacol Sci. 2019 Dec;40(12):911-918. doi: 10.1016/j.tips.2019.10.001. Epub 2019 Nov 5.
本文引用的文献
1
A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models.TRPC5离子通道的小分子抑制剂可抑制动物模型中的进行性肾病。
Science. 2017 Dec 8;358(6368):1332-1336. doi: 10.1126/science.aal4178.
2
Chronic kidney disease.慢性肾脏病。
Nat Rev Dis Primers. 2017 Nov 23;3:17088. doi: 10.1038/nrdp.2017.88.
3
Chronic Kidney Disease.慢性肾脏病。
Lancet. 2017 Mar 25;389(10075):1238-1252. doi: 10.1016/S0140-6736(16)32064-5. Epub 2016 Nov 23.
4
Synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-a]benzimidazole derivatives against Leishmania donovani and Trypanosoma cruzi.2,3-二氢咪唑并[1,2-a]苯并咪唑衍生物的合成及抗利什曼原虫和克氏锥虫的生物评价。
Eur J Med Chem. 2014 Sep 12;84:395-403. doi: 10.1016/j.ejmech.2014.07.038. Epub 2014 Jul 11.
5
Inhibition of the TRPC5 ion channel protects the kidney filter.抑制 TRPC5 离子通道可保护肾脏滤器。
J Clin Invest. 2013 Dec;123(12):5298-309. doi: 10.1172/JCI71165. Epub 2013 Nov 15.
6
When a TRP goes bad: transient receptor potential channels in addiction.当瞬时受体电位通道（TRP）出现异常：成瘾中的瞬时受体电位通道。
Life Sci. 2013 Mar 19;92(8-9):410-4. doi: 10.1016/j.lfs.2012.07.008. Epub 2012 Jul 20.
7
Focal segmental glomerulosclerosis.局灶节段性肾小球硬化症
N Engl J Med. 2011 Dec 22;365(25):2398-411. doi: 10.1056/NEJMra1106556.
8
Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels.鉴定 ML204，一种新型强效拮抗剂，可选择性调节天然 TRPC4/C5 离子通道。
J Biol Chem. 2011 Sep 23;286(38):33436-46. doi: 10.1074/jbc.M111.274167. Epub 2011 Jul 27.
9
The mammalian TRPC cation channels.哺乳动物的瞬时受体电位阳离子通道。
Biochim Biophys Acta. 2004 Dec 6;1742(1-3):21-36. doi: 10.1016/j.bbamcr.2004.08.015.
10
Rapid vesicular translocation and insertion of TRP channels.瞬时受体电位（TRP）通道的快速囊泡转运与插入
Nat Cell Biol. 2004 Aug;6(8):709-20. doi: 10.1038/ncb1150. Epub 2004 Jul 18.
Zotero 插件