<br>SC-560 和莫非唑酸电子等排体作为具有抗血小板作用的新型有效 COX-1 选择性抑制剂,Archiv der Pharmazie

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SC-560 和莫非唑酸电子等排体作为具有抗血小板作用的新型有效 COX-1 选择性抑制剂
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2023-02-11 , DOI: 10.1002/ardp.202200549
Miroslav Sisa ₁ , Lukáš Konečný ₂ , Veronika Temml ₃ , Alejandro Carazo ₂ , Přemysl Mladěnka ₂ , Přemysl Landa ₁

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选择性环氧合酶（COX）-1抑制剂可作为潜在的心脏保护药物。此外，COX-1 在炎症过程中发挥着关键作用，其活性与某些类型的癌症有关。在这项工作中，我们设计并合成了一组在结构上模仿选择性 COX-1 抑制剂 SC-560 和莫非唑酸的化合物，其中心核心被三唑或苯环取代。与母体化合物的合成相比，该方法的优点是合成相对简单。新合成的化合物在体外酶测定中对COX-1表现出显着的活性和选择性。最有效的化合物10a （COX-1 的 IC ₅₀ = 3 nM，COX-2 的 IC 50 = 850 nM）与 SC-560 一样活跃（COX-1 的 IC ₅₀ = 2.4 nM，COX-2 的 IC 50 = 470 nM） COX-1 的选择性更强。体外 COX-1 酶活性在基于细胞的全血抗血小板测定中得到进一步证实，其中四种选定化合物中的三种（ 10a、c、d和3b ）在纳摩尔范围内发挥了出色的 IC ₅₀值（9 –252 nm）。此外，进行对接模拟以揭示 COX-1 结合袋内的关键相互作用。此外，使用正常人肾HK-2细胞系测试了所选化合物的毒性。

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SC-560 and mofezolac isosteres as new potent COX-1 selective inhibitors with antiplatelet effect

Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC₅₀ = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC₅₀ = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC₅₀ values in the nanomolar range (9–252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.

更新日期：2023-02-11

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