As a γ-aminobutyric acid A receptor (GABAR) inhibitor, etomidate fulfills several characteristics of an ideal anesthetic agent, such as rapid onset with rapid clearance and high potency, along with cardiovascular stability. Unfortunately, etomidate has been reported to inhibit CYP11B1 at hypnotic doses, which is associated with a marked increase in patient deaths due to this unexpected off-target effect. In this study, molecular docking was used to simulate the binding mode of etomidate with GABAR and CYP11B1. Based on the in-depth analysis of the binding mode, strong electron-withdrawing group on the C4 position of the imidazole ring was introduced to reduce the charge density of the nitrogen, which is beneficial in reducing the coordination bond between the imidazole nitrogen and heme iron in CYP11B1, as well as in reducing the adrenocortical suppression. Based on the results of ADMET property prediction, MEP analysis, and molecular docking simulation, 4-fluoroetomidate (EL-0052) was designed and synthesized. studies in rats and mice confirmed that EL-0052 had the efficacy similar to etomidate, but without adrenocortical suppression. These findings suggested that EL-0052 was superior to etomidate and support the continued development of EL-0052 as a preclinical candidate as an anesthetic.

中文翻译：

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发现 EL-0052 作为一种潜在的麻醉药物


作为 γ-氨基丁酸 A 受体 (GABAR) 抑制剂，依托咪酯具有理想麻醉剂的几个特征，例如起效快、清除快、效力高以及心血管稳定性。不幸的是，据报道，依托咪酯在催眠剂量下会抑制 CYP11B1，由于这种意想不到的脱靶效应，患者死亡人数显着增加。本研究采用分子对接模拟依托咪酯与GABAR和CYP11B1的结合模式。在深入分析结合模式的基础上，在咪唑环C4位引入强吸电子基团，降低氮的电荷密度，有利于减少咪唑氮与血红素之间的配位键CYP11B1 中的铁，以及减少肾上腺皮质抑制。基于ADMET性质预测、MEP分析和分子对接模拟的结果，设计并合成了4-氟依托咪酯（EL-0052）。对大鼠和小鼠的研究证实，EL-0052 具有与依托咪酯类似的功效，但没有肾上腺皮质抑制作用。这些发现表明 EL-0052 优于依托咪酯，并支持 EL-0052 作为临床前候选麻醉剂的持续开发。