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Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors
新型天冬氨酸衍生物作为高效选择性FXIa抑制剂的发现
高効率選択性FXIa阻害剤としての新規アスパラギン誘導体の発見
신형 텐동아미노산 파생물질이 고효율 선택성 FXIA 억제제로서의 발견
Descubrimiento de nuevos derivados del ácido aspártico como Inhibidores selectivos de fxia de alta eficiencia
Découverte de nouveaux dérivés de l'acide aspartique comme inhibiteurs sélectifs de fxia à haut rendement
обнаружение новых производных аминокислоты в качестве высокоселективного ингибитора FXIA
Ling Zhang 章凌 ¹, Wei Chen 陈威 ², Ningning Yao 姚宁宁 ¹, Shuzeng Hou 侯书增 ¹, Zhiwei Meng 孟志伟 ¹, Yi Kong 孔毅 ², Chenzhong Liao 廖晨钟 ¹, Zhouling Xie 谢周令 ¹
¹ Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
中国 合肥 合肥工业大学 食品与生物工程学院 药物科学与工程系
² School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
中国 南京 中国药科大学生命科学与技术学院
Journal of Chinese Pharmaceutical Sciences, 31 October 2022
Abstract

As a coagulation factor in the intrinsic coagulation pathway, factor XIa (FXIa) is an effective and safe target for the development of antithrombotic drugs. Many small-molecule FXIa inhibitors have been discovered, some of which are being evaluated in clinical trials. However, none of them have been approved.

In the present study, a highly selective potent FXIa inhibitor with poor solubility reported in our previous work was selected as a lead compound to be further modified to improve FXIa potency and physicochemical properties. The structure-based drug design and structure-activity relationship study led to the discovery of LY8, LY17, and LY25, which demonstrated enhanced FXIa potency and maintained excellent selectivity.

In addition, LY8 exhibited significantly improved aqueous solubility, suggesting that it could be a promising compound to be further evaluated.
Journal of Chinese Pharmaceutical Sciences_1
Journal of Chinese Pharmaceutical Sciences_2
Journal of Chinese Pharmaceutical Sciences_3
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