新型双芳基磺酰胺和芳基磺酰亚胺作为纤溶酶原激活物抑制剂-1（PAI-1）的失活剂。
Novel bis-arylsulfonamides and aryl sulfonimides as inactivators of plasminogen activator inhibitor-1 (PAI-1).
机构信息
Department of Chemistry, Eastern Michigan University, 225 Mark Jefferson, Ypsilanti, MI 48197, United States.
出版信息
Bioorg Med Chem Lett. 2010 Feb 1;20(3):966-70. doi: 10.1016/j.bmcl.2009.12.051. Epub 2009 Dec 21.
Abstract
Inactivators of plasminogen activator inhibitor-1 (PAI-1) have been identified as possible treatments for a range of conditions, including atherosclerosis, venous thrombosis, and obesity. We describe the synthesis and inhibitory activity of a novel series of compounds based on bis-arylsulfonamide and aryl sulfonimide motifs that show potent and specific activity towards PAI-1. Inhibitors containing short linking units between the sulfonyl moieties and a 3,4-dihydroxy aryl substitution pattern showed the most potent inhibitory activity, and retained high specificity for PAI-1 over the structurally-related serpin anti-thrombin III (ATIII).
摘要
纤溶酶原激活物抑制剂-1（PAI-1）的失活剂已被确定为治疗多种疾病的可能方法，包括动脉粥样硬化、静脉血栓形成和肥胖症。我们描述了一系列基于双芳基磺酰胺和芳基磺酰亚胺基序的新型化合物的合成和抑制活性，这些化合物对 PAI-1 表现出强效和特异性。在磺酰基之间具有短连接单元并且具有 3,4-二羟基芳基取代模式的抑制剂表现出最强的抑制活性，并且对结构相关的丝氨酸蛋白酶抗凝血酶 III（ATIII）具有很高的特异性。
相似文献
1
Novel bis-arylsulfonamides and aryl sulfonimides as inactivators of plasminogen activator inhibitor-1 (PAI-1).新型双芳基磺酰胺和芳基磺酰亚胺作为纤溶酶原激活物抑制剂-1（PAI-1）的失活剂。
Bioorg Med Chem Lett. 2010 Feb 1;20(3):966-70. doi: 10.1016/j.bmcl.2009.12.051. Epub 2009 Dec 21.
2
Identification of a conformationally distinct form of plasminogen activator inhibitor-1, acting as a noninhibitory substrate for tissue-type plasminogen activator.
J Biol Chem. 1992 Jun 15;267(17):11693-6.
3
Identification of the binding site for a low-molecular-weight inhibitor of plasminogen activator inhibitor type 1 by site-directed mutagenesis.通过定点诱变鉴定1型纤溶酶原激活物抑制剂低分子量抑制剂的结合位点。
Biochemistry. 1998 Feb 3;37(5):1227-34. doi: 10.1021/bi971554q.
4
5
Expression of tissue type and urokinase type plasminogen activators as well as plasminogen activator inhibitor type-1 and type-2 in human and rhesus monkey placenta.组织型和尿激酶型纤溶酶原激活剂以及纤溶酶原激活剂抑制剂-1和-2在人和恒河猴胎盘中的表达
J Anat. 1999 Feb;194 ( Pt 2)(Pt 2):183-95. doi: 10.1046/j.1469-7580.1999.19420183.x.
6
Biological mechanisms underlying the clinical effects of RU 486: modulation of cultured endometrial stromal cell plasminogen activator and plasminogen activator inhibitor expression.RU 486临床效应的生物学机制：对培养的子宫内膜基质细胞纤溶酶原激活物及纤溶酶原激活物抑制剂表达的调节
J Clin Endocrinol Metab. 1995 Apr;80(4):1100-5. doi: 10.1210/jcem.80.4.7714076.
7
Characterization and comparative evaluation of a structurally unique PAI-1 inhibitor exhibiting oral in-vivo efficacy.一种具有口服体内疗效的结构独特的纤溶酶原激活物抑制剂-1（PAI-1）抑制剂的表征及比较评价
J Thromb Haemost. 2004 Aug;2(8):1422-8. doi: 10.1111/j.1538-7836.2004.00829.x.
8
Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats: role of stellate cells.大鼠肝纤维化形成过程中纤溶酶原激活物及纤溶酶原激活物抑制剂表达增加：星状细胞的作用
J Hepatol. 1999 Oct;31(4):703-11. doi: 10.1016/s0168-8278(99)80351-1.
9
Prostaglandin E2 regulates production of plasminogen activator isoenzymes, urokinase receptor, and plasminogen activator inhibitor-1 in primary cultures of rat calvarial osteoblasts.前列腺素E2调节大鼠颅骨成骨细胞原代培养物中纤溶酶原激活物同工酶、尿激酶受体和纤溶酶原激活物抑制剂-1的产生。
J Cell Physiol. 1995 Dec;165(3):521-9. doi: 10.1002/jcp.1041650310.
10
Inhibition of plasminogen activator inhibitor-1 is a potential therapeutic strategy in ovarian cancer.抑制纤溶酶原激活物抑制剂-1是卵巢癌的一种潜在治疗策略。
Cancer Biol Ther. 2015;16(2):253-60. doi: 10.1080/15384047.2014.1001271.
引用本文的文献
1
Pharmaceutical and medicinal significance of sulfur (S)-Containing motifs for drug discovery: A critical review.含硫（S）结构在药物研发中的药用和药物学意义：批判性评价。
Eur J Med Chem. 2019 Jan 15;162:679-734. doi: 10.1016/j.ejmech.2018.11.017. Epub 2018 Nov 22.
2
Effects of altered plasminogen activator inhibitor-1 expression on cardiovascular disease.纤溶酶原激活物抑制剂-1 表达改变对心血管疾病的影响。
Curr Drug Targets. 2011 Nov;12(12):1782-9. doi: 10.2174/138945011797635803.
3
From bifunctional to trifunctional (tricomponent nucleophile-transition metal-lewis acid) catalysis: the catalytic, enantioselective α-fluorination of acid chlorides.从双功能到三功能（三组分亲核体-过渡金属-路易斯酸）催化：酰氯的催化、对映选择性α-氟化反应。
J Am Chem Soc. 2011 May 18;133(19):7536-46. doi: 10.1021/ja2014345. Epub 2011 Apr 22.
本文引用的文献
1
Characterization of a novel class of polyphenolic inhibitors of plasminogen activator inhibitor-1.新型类多酚抑制剂对纤溶酶原激活物抑制剂-1 的作用特征。
J Biol Chem. 2010 Mar 12;285(11):7892-902. doi: 10.1074/jbc.M109.067967. Epub 2010 Jan 8.
2
Role of fibrinolysis in obesity and thrombosis.纤维蛋白溶解在肥胖与血栓形成中的作用。
Thromb Res. 2009;123 Suppl 4:S46-9. doi: 10.1016/S0049-3848(09)70143-4.
3
Dose-dependent thrombus resolution due to oral plaminogen activator inhibitor (PAI)-1 inhibition with tiplaxtinin in a rat stenosis model of venous thrombosis.在大鼠静脉血栓形成狭窄模型中，替普拉西丁抑制口服纤溶酶原激活物抑制剂（PAI）-1可导致剂量依赖性血栓溶解。
Thromb Haemost. 2008 Apr;99(4):749-58. doi: 10.1160/TH07-11-0669.
4
Protection from high fat diet-induced increase in ceramide in mice lacking plasminogen activator inhibitor 1.缺乏纤溶酶原激活物抑制剂1的小鼠对高脂饮食诱导的神经酰胺增加具有保护作用。
J Biol Chem. 2008 May 16;283(20):13538-48. doi: 10.1074/jbc.M709950200. Epub 2008 Mar 22.
5
Inhibition of plasminogen activator inhibitor-1: its mechanism and effectiveness on coagulation and fibrosis.纤溶酶原激活物抑制剂-1的抑制作用：其作用机制及对凝血和纤维化的影响
Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):672-7. doi: 10.1161/ATVBAHA.107.157479. Epub 2008 Jan 31.
6
A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy.一种纤溶酶原激活物抑制剂-1（PAI-1）突变体PAI-1R可减缓糖尿病肾病的进展。
J Am Soc Nephrol. 2008 Feb;19(2):329-38. doi: 10.1681/ASN.2007040510. Epub 2008 Jan 23.
7
S35225 is a direct inhibitor of Plasminogen Activator Inhibitor type-1 activity in the blood.S35225是血液中纤溶酶原激活物抑制剂-1活性的直接抑制剂。
Thromb Res. 2008;122(2):265-70. doi: 10.1016/j.thromres.2007.11.006. Epub 2008 Feb 21.
8
PAI-1 - a potential therapeutic target in cancer.纤溶酶原激活物抑制剂-1——癌症的一个潜在治疗靶点。
Curr Drug Targets. 2007 Sep;8(9):1030-41. doi: 10.2174/138945007781662346.
9
Neutralization of plasminogen activator inhibitor I (PAI-1) by the synthetic antagonist PAI-749 via a dual mechanism of action.合成拮抗剂PAI-749通过双重作用机制对纤溶酶原激活物抑制剂I（PAI-1）进行中和。
Mol Pharmacol. 2007 Oct;72(4):897-906. doi: 10.1124/mol.107.037010. Epub 2007 Jul 10.
10
Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor.小分子抑制剂使纤溶酶原激活物抑制剂-1失活的机制
J Biol Chem. 2007 Mar 23;282(12):9288-96. doi: 10.1074/jbc.M611642200. Epub 2007 Feb 2.
Zotero 插件