Structurally Minimalized and Druglike TGase2 Inhibitors Based on 7-Aminoquinoline-5,8-dione Scaffolds for the Treatment of Diabetic Retinopathy

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Jihee Kang, Hye-Yoon Jeon, Jieon Lee, Seri Bae, Ga Young Park, Kyoung-jin Min, Jeongmin Joo, Ah-Jun Lee, Hyo-Ji Kim, Chun Young Im, Eun-Bin Kim, Ji Hun Lee, Ji Sun Hwang, Seungju Lee, Jee-Young Lee, Pauline Navals, Jeffrey W. Keillor, Kwon-Soo Ha, Minsoo Song
{"title":"Structurally Minimalized and Druglike TGase2 Inhibitors Based on 7-Aminoquinoline-5,8-dione Scaffolds for the Treatment of Diabetic Retinopathy","authors":"Jihee Kang, Hye-Yoon Jeon, Jieon Lee, Seri Bae, Ga Young Park, Kyoung-jin Min, Jeongmin Joo, Ah-Jun Lee, Hyo-Ji Kim, Chun Young Im, Eun-Bin Kim, Ji Hun Lee, Ji Sun Hwang, Seungju Lee, Jee-Young Lee, Pauline Navals, Jeffrey W. Keillor, Kwon-Soo Ha, Minsoo Song","doi":"10.1021/acs.jmedchem.4c02081","DOIUrl":null,"url":null,"abstract":"Diabetic retinopathy is a disease that can cause vision loss leading to blindness in people with diabetes. Improved methods to treat and prevent vision loss in diabetic patients are in high demand owing to limited current treatment procedures. Herein, we report a new class of transglutaminase 2 (TGase2) inhibitors for the treatment of diabetic retinopathy based on 7-aminoquinoline-5,8-dione derivatives. 7-Amino-2-phenylquinoline-5,8-dione <b>11</b> and 7-amino-2-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}quinoline-5,8-dione <b>23</b> exhibited potent inhibitory activities against TGase2 in a fibrinogen array-based on-chip TGase2 activity assay and in an in situ assay in human retinal microvascular endothelial cells, with IC<sub>50</sub> values of 5.88 and 1.12 μM in vitro, and 0.09 and 0.07 μM in situ, respectively. Pharmacokinetically favorable 7-amino-2-{4-[(1-isopropylpiperidin-4-yl)oxy] phenyl}quinoline-5,8-dione <b>22</b> inhibited vascular leakage in the retinas of streptozotocin-induced diabetic mice via oral administration. Results from the AL5 kinetic assay and a molecular docking study suggest that the inhibitors may bind to TGase2 remote from the active site.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c02081","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

Abstract

Diabetic retinopathy is a disease that can cause vision loss leading to blindness in people with diabetes. Improved methods to treat and prevent vision loss in diabetic patients are in high demand owing to limited current treatment procedures. Herein, we report a new class of transglutaminase 2 (TGase2) inhibitors for the treatment of diabetic retinopathy based on 7-aminoquinoline-5,8-dione derivatives. 7-Amino-2-phenylquinoline-5,8-dione 11 and 7-amino-2-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}quinoline-5,8-dione 23 exhibited potent inhibitory activities against TGase2 in a fibrinogen array-based on-chip TGase2 activity assay and in an in situ assay in human retinal microvascular endothelial cells, with IC50 values of 5.88 and 1.12 μM in vitro, and 0.09 and 0.07 μM in situ, respectively. Pharmacokinetically favorable 7-amino-2-{4-[(1-isopropylpiperidin-4-yl)oxy] phenyl}quinoline-5,8-dione 22 inhibited vascular leakage in the retinas of streptozotocin-induced diabetic mice via oral administration. Results from the AL5 kinetic assay and a molecular docking study suggest that the inhibitors may bind to TGase2 remote from the active site.

Abstract Image

用于治疗糖尿病视网膜病变的基于 7-氨基喹啉-5,8-二酮支架的结构最小化和药物样 TGase2 抑制剂
糖尿病视网膜病变是一种可导致糖尿病患者视力下降并最终失明的疾病。由于目前的治疗方法有限,因此需要改进治疗和预防糖尿病患者视力丧失的方法。在此,我们报告了一类基于 7-氨基喹啉-5,8-二酮衍生物的治疗糖尿病视网膜病变的新型转谷氨酰胺酶 2(TGase2)抑制剂。7-氨基-2-苯基喹啉-5,8-二酮 11 和 7-氨基-2-{4-[(1-甲基哌啶-4-基)氧基]苯基}喹啉-5,8-二酮 23 在基于纤维蛋白原阵列的片上 TGase2 活性测定和人视网膜微血管内皮细胞原位测定中表现出对 TGase2 的强效抑制活性,IC50 值分别为 5.体外的 IC50 值分别为 5.88 和 1.12 μM,原位的 IC50 值分别为 0.09 和 0.07 μM。药代动力学上有利的 7-氨基-2-{4-[(1-异丙基哌啶-4-基)氧基]苯基}喹啉-5,8-二酮 22 通过口服可抑制链脲佐菌素诱导的糖尿病小鼠视网膜的血管渗漏。AL5 动力学测定和分子对接研究的结果表明,这些抑制剂可能与远离活性位点的 TGase2 结合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信