以天冬氨酸为母核的高活性高选择性FXIa抑制剂的发现

doi:10.5246/jcps.2022.10.062

中国药学(英文版) ›› 2022, Vol. 31 ›› Issue (10): 727-737.DOI: 10.5246/jcps.2022.10.062

• 【研究论文】 • 下一篇

以天冬氨酸为母核的高活性高选择性FXIa抑制剂的发现

章凌¹^,^#, 陈威²^,^#, 姚宁宁¹, 侯书增¹^,², 孟志伟¹, 孔毅², 廖晨钟¹^,^*(), 谢周令¹^,^*()

1. 合肥工业大学食品与生物工程学院药物科学与工程系, 安徽合肥 230009
2. 中国药科大学生命科学与技术学院, 江苏南京 210009

收稿日期:2022-07-21 修回日期:2022-08-15 接受日期:2022-08-25 出版日期:2022-10-31 发布日期:2022-10-31
通讯作者: 廖晨钟, 谢周令
作者简介:
+ Tel.: +86-15850673817, E-mail: zhoulingxie@hfut.edu.cn
+ Tel.: +86-18256007962, E-mail: czliao@hfut.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81803352).

Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors

Ling Zhang¹^,^#, Wei Chen²^,^#, Ningning Yao¹, Shuzeng Hou¹^,², Zhiwei Meng¹, Yi Kong², Chenzhong Liao¹^,^*(), Zhouling Xie¹^,^*()

1 Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
2 School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China

Received:2022-07-21 Revised:2022-08-15 Accepted:2022-08-25 Online:2022-10-31 Published:2022-10-31
Contact: Chenzhong Liao, Zhouling Xie
About author:
# Ling Zhang and Wei Chen contributed to this work equally.

摘要/Abstract

摘要：

作为内源性凝血途径中的凝血因子, FXIa因子是开发抗血栓药物有效和安全的靶点。迄今为止, 已经有多类小分子FXIa抑制剂被报道, 其中几个正处于临床试验中, 但没有药物获批。本文选择了我们课题组报道的一个高活性高选择性但水溶性较差的FXIa抑制剂作为先导化合物, 以进一步提高对FXIa的活性、选择性和物理化学性质。基于结构的药物设计以及构效关系研究发现了LY8、LY17和LY25三个化合物, 它们在保持了很好的选择性的同时, 提高了对FXIa的抑制作用。同时, LY8还表现出显著改善的水溶性, 为进一步开发安全有效的抗凝血药物奠定了基础。

关键词: 抗血栓, 抗凝血药物, FXIa因子, 出血风险, 构效关系

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.

Key words: Antithrombosis, Anticoagulants, Factor XIa, Bleeding risk, Structure-activity relationship

Supporting:

章凌, 陈威, 姚宁宁, 侯书增, 孟志伟, 孔毅, 廖晨钟, 谢周令. 以天冬氨酸为母核的高活性高选择性FXIa抑制剂的发现[J]. 中国药学(英文版), 2022, 31(10): 727-737.

Ling Zhang, Wei Chen, Ningning Yao, Shuzeng Hou, Zhiwei Meng, Yi Kong, Chenzhong Liao, Zhouling Xie. Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(10): 727-737.

图/表 9

Figure 1. Chemical structures of FXIa inhibitors in clinical studies (1–5) and compound 6 reported in our previous study.

Figure 2. (A) Docking model of compound 6 with FXIa (PDB: 5QCN); (B) A structure-activity relationship study on compound 6.

Scheme 1. Preparation of LY1–LY5. Reagents and conditions: (i) aniline derivatives (0.9 equiv.), pyridine (6.0 equiv.), POCl3 (1.1 equiv.), DCM, 0 °C, 30 min; (ii) Pd/C (10%), H2, MeOH, rt, 12 h; (iii) N-phenylpiperazine (1.5 equiv.), HBTU (1.2 equiv.), DIPEA (3.0 equiv.), DCM, rt, overnight; (iv) TFA (5.0 equiv.), DCM, rt, overnight; (v) 3-chlorocinnamate derivatives (0.7 equiv.), HBTU (0.8 equiv.), DIPEA (1.0 equiv.), DMF, rt, 12 h.

Scheme 2. Preparation of h1–h5. Reagents and conditions: (i) R4-Br (1.0 equiv.), Cs2CO3 (2.0 equiv.), BINAP (0.09 equiv.), Pd(OAc)2 (0.016 equiv.), 80 °C, N2, 1,4-dioxane, overnight; (ii) TFA (5.0 equiv.), DCM, rt, overnight.

Scheme 3. Preparation of LY6–LY31. Reagents and conditions: (i) 1-phenylpiperazine derivatives or 4-phenylpiperidine (1.5 equiv.), HBTU (1.2 equiv.), DIPEA (3.0 equiv.), DCM, rt, overnight; (ii) TFA (5.0 equiv.), DCM, rt, overnight; (iii) (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid (0.67 equiv.), HBTU (0.8 equiv.), DIPEA (1.0 equiv.), DMF, rt, 12 h.

Table 1. Inhibitory activity against FXIa of LY1–LY5.

Table 2. Inhibitory activity against FXIa of LY6–LY30.

Figure 3. Docking models of LY17 (A) and LY25 (B) with FXIa. Ligands (compound 6: yellow, LY17: green, LY25: cyan) are shown as stick and ball modes. Residues are shown as orange stick modes. The indirect hydrogen bonds between compounds and FXIa are not shown because all water molecules were removed before compounds were docked into FXIa.

Table 3. Selectivity profiles and aqueous solubility of LY8, LY17, and LY25.

参考文献 21

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以天冬氨酸为母核的高活性高选择性FXIa抑制剂的发现

Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors

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