Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia,ChemistryOpen

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Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia
ChemistryOpen ( IF 2.5 ) Pub Date : 2020-11-10 , DOI: 10.1002/open.202000277
Srabani Kar ₁ , Madhusoodanan Mottamal ₂ , Rami A Al-Horani ₁

Affiliation

The inhibition of factor XIa (FXIa) is a trending paradigm for the development of new generations of anticoagulants without a substantial risk of bleeding. In this report, we present the discovery of a benzyl tetra‐phosphonate derivative as a potent and selective inhibitor of human FXIa. Biochemical screening of four phosphonate/phosphate derivatives has led to the identification of the molecule that inhibited human FXIa with an IC₅₀ value of ∼7.4 μM and a submaximal efficacy of ∼68 %. The inhibitor was at least 14‐fold more selective to FXIa over thrombin, factor IXa, factor Xa, and factor XIIIa. It also inhibited FXIa‐mediated activation of factor IX and prolonged the activated partial thromboplastin time of human plasma. In Michaelis‐Menten kinetics experiment, inhibitor 1 reduced the V_MAX of FXIa hydrolysis of a chromogenic substrate without significantly affecting its K_M suggesting an allosteric mechanism of inhibition. The inhibitor also disrupted the formation of FXIa – antithrombin complex and inhibited thrombin‐mediated and factor XIIa‐mediated formation of FXIa from its zymogen factor XI. Inhibitor 1 has been proposed to bind to or near the heparin/polyphosphate‐binding site in the catalytic domain of FXIa. Overall, inhibitor 1 is the first benzyl tetraphosphonate small molecule that allosterically inhibits human FXIa, blocks its physiological function, and prevents its zymogen activation by other clotting factors under in vitro conditions. Thus, we put forward benzyl tetra‐phosphonate 1 as a novel lead inhibitor of human FXIa to guide future efforts in the development of allosteric anticoagulants.

中文翻译：

发现四膦酸苄酯衍生物作为人类 Xia 因子抑制剂

XIa 因子 (FXIa) 的抑制是新一代抗凝剂开发的趋势范例，且不会产生重大出血风险。在本报告中，我们发现了四膦酸苄酯衍生物作为人 FXIa 的有效选择性抑制剂。对四种膦酸盐/磷酸盐衍生物的生化筛选已鉴定出抑制人 FXIa 的分子，其IC ₅₀值为 ∼7.4 μM，次最大功效为 ∼68%。该抑制剂对 FXIa 的选择性比凝血酶、因子 IXa、因子 Xa 和因子 XIIIa 至少高 14 倍。它还抑制 FXIa 介导的因子 IX 的激活，并延长人血浆的活化部分凝血活酶时间。在 Michaelis-Menten 动力学实验中，抑制剂1降低了显色底物 FXIa 水解的 V _MAX ，但没有显着影响其 K _M ，表明存在变构抑制机制。该抑制剂还破坏 FXIa - 抗凝血酶复合物的形成，并抑制凝血酶介导和因子 XIIa 介导的酶原因子 XI 形成 FXIa。抑制剂1已被提议与 FXIa 催化结构域中的肝素/聚磷酸盐结合位点或附近结合。总体而言，抑制剂1是第一个在体外条件下变构抑制人FXIa、阻断其生理功能并防止其酶原被其他凝血因子激活的四膦酸苄酯小分子。因此，我们提出四膦酸苄酯1作为人 FXIa 的新型先导抑制剂，以指导未来变构抗凝剂的开发工作。

更新日期：2020-11-12

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