新型[3.3.1]双环磺酰胺-吡唑类γ-分泌酶抑制剂的设计、合成及构效关系研究。

Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent γ-secretase inhibitors.

机构信息

Department of Medicinal Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States.

出版信息

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5791-4. doi: 10.1016/j.bmcl.2011.08.008. Epub 2011 Aug 9.

DOI:10.1016/j.bmcl.2011.08.008

Abstract

The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.

摘要

本文详细介绍了一系列新型、有效且代谢稳定的磺胺吡唑类化合物的结构-活性关系（SAR），这些化合物通过γ-分泌酶抑制来减弱β-淀粉样肽的合成。通过单次口服给药，磺胺吡唑类化合物能够有效降低 FVB 小鼠皮质 Aβx-40 水平，并且磺胺吡唑类化合物对 γ-分泌酶抑制 APP 与 Notch 加工具有选择性，这些化合物得到了重点强调。

相似文献

1

Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent γ-secretase inhibitors.新型[3.3.1]双环磺酰胺-吡唑类γ-分泌酶抑制剂的设计、合成及构效关系研究。

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5791-4. doi: 10.1016/j.bmcl.2011.08.008. Epub 2011 Aug 9.

2

Design, synthesis, and structure-activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline gamma-secretase inhibitors.新型口服有效的基于吡唑/磺酰胺的二氢喹啉γ-分泌酶抑制剂的设计、合成及构效关系

Bioorg Med Chem Lett. 2009 Sep 1;19(17):4920-3. doi: 10.1016/j.bmcl.2009.07.092. Epub 2009 Jul 23.

3

Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-pyrazoles as potent, selective and efficacious γ-secretase inhibitors.发现一种新型[3.2.1]苯并稠合双环磺酰胺-吡唑类化合物，作为有效、选择性的γ-分泌酶抑制剂。

Bioorg Med Chem Lett. 2013 Feb 15;23(4):996-1000. doi: 10.1016/j.bmcl.2012.12.039. Epub 2012 Dec 21.

4

Amino-caprolactam γ-secretase inhibitors showing potential for the treatment of Alzheimer's disease.具有治疗阿尔茨海默病潜力的氨基己内酰胺 γ-分泌酶抑制剂。

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3715-20. doi: 10.1016/j.bmcl.2011.04.079. Epub 2011 May 1.

5

Design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors.作为γ-分泌酶抑制剂的四氢喹啉和吡咯烷磺酰胺氨基甲酸酯的设计、合成及评估

Bioorg Med Chem Lett. 2007 Jun 1;17(11):3010-3. doi: 10.1016/j.bmcl.2007.03.055. Epub 2007 Mar 23.

6

Synthesis and structure-activity relationship of a novel series of heterocyclic sulfonamide gamma-secretase inhibitors.新型杂环磺酰胺γ-分泌酶抑制剂的合成及其构效关系

Bioorg Med Chem. 2009 Jul 1;17(13):4708-17. doi: 10.1016/j.bmc.2009.04.052. Epub 2009 May 3.

7

Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors.发现新型磺酰胺-吡唑并哌啶系列作为有效和高效的γ-分泌酶抑制剂。

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2195-9. doi: 10.1016/j.bmcl.2010.02.039. Epub 2010 Feb 13.

8

Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease.贝加西他（GSI-953）：一种新型的、选择性的噻吩磺酰胺类淀粉样前体蛋白γ-分泌酶抑制剂，用于治疗阿尔茨海默病。

J Pharmacol Exp Ther. 2009 Nov;331(2):598-608. doi: 10.1124/jpet.109.152975. Epub 2009 Aug 11.

9

Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch.（R）-4-环丙基-7,8-二氟-5-[4-（三氟甲基）苯磺酰基]-4,5-二氢-1H-吡唑并[4,3-c]喹啉（ELND006）和（R）-4-环丙基-8-氟-5-[6-（三氟甲基）吡啶-3-基磺酰基]-4,5-二氢-2H-吡唑并[4,3-c]喹啉（ELND007）的发现：代谢稳定的γ-分泌酶抑制剂，选择性抑制淀粉样蛋白-β的产生，而不影响 Notch。

J Med Chem. 2013 Jul 11;56(13):5261-74. doi: 10.1021/jm301741t. Epub 2013 Jun 20.

10

Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.用于治疗阿尔茨海默病的Notch-1保留型γ-分泌酶抑制剂贝加西他的发现。

J Med Chem. 2008 Dec 11;51(23):7348-51. doi: 10.1021/jm801252w.

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验