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Design and synthesis of novel factor XIa Inhibitors with bicyclic isoquinoline and naphthalene fragments

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Abstract

FXIa has emerged as a promising therapeutic target for treating thrombotic diseases. With the aim to replace the aniline motif of asundexian with novel P2’ fragments, bicyclic isoquinoline and naphthalene rings were designed. The target compounds with isoquinoline ring were synthesized via 13 steps of chemical reactions. Substituents within the rings were investigated to elucidate the structural determinants governing selective or dual inhibition of FXIa and Plasma Kallikrein (PKa). In vitro testing showed that some of the designed compounds exhibited comparable potency against both FXIa and PKa, while others achieved up to 94-fold selectivity. Analysis of structure-activity relationships (SARs) uncovered the pivotal role of the carboxylic acid moiety in retaining inhibition of FXIa and PKa, and the steric hindrance and hydrogen-bond receptor functional groups were identified as key factors influencing the selectivity of FXIa inhibition over PKa. The docking study additionally unveiled different binding modes that play a significant role in the observed activity and selectivity. Furthermore, the selected compounds significantly extended the plasma coagulation time in a dose-dependent manner. Altogether, the bicyclic compounds may be promising lead compounds for the development of highly effective FXIa inhibitors.

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Acknowledgements

We thank the financial support from the National Natural Science Foundation of China (22107082), the Natural Science Foundation of SiChuan (2024NSFSC0290), the Sichuan Science and Technology Program (2021YFG0111), and Sichuan Province’s Central Government-led Local Science and Technology Development Project (2021ZYD0058).

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  1. College of Chemistry and Material Science, Sichuan Normal University, Chengdu, Sichuan, 610068, China

    Yi Zhang, Linjun Dai, Yi Tan, Yongpeng Yu, Feng Yang, Boquan Ren, Yan-Jun Xu & Qing Li

  2. Department of Organic Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nan**g, 210009, China

    Junhao **ng

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Zhang, Y., Dai, L., Tan, Y. et al. Design and synthesis of novel factor XIa Inhibitors with bicyclic isoquinoline and naphthalene fragments. Med Chem Res 33, 1003–1023 (2024). https://doi.org/10.1007/s00044-024-03245-9

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