Nhwa Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Corporation Ltd., Xuzhou, China (X.X., Y.D., Y.Q., Z.M.); School of Pharmacy, Xuzhou Medical University, Xuzhou, China (Y.W.); Jiangsu Nhwa-Luokang Pharma R&D Ltd. Chongqing, China (K.W., J.X., T.W., L.Z., X.D., Y.S., Q.L.); The Key Laboratory of Biochemistry and Molecular Pharmacology (W.J.), and Division of Medicinal Chemistry (Q.L.), School of Pharmacy, Chongqing Medical University, Chongqing, China.
Nhwa Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Corporation Ltd., Xuzhou, China (X.X., Y.D., Y.Q., Z.M.); School of Pharmacy, Xuzhou Medical University, Xuzhou, China (Y.W.); Jiangsu Nhwa-Luokang Pharma R&D Ltd. Chongqing, China (K.W., J.X., T.W., L.Z., X.D., Y.S., Q.L.); The Key Laboratory of Biochemistry and Molecular Pharmacology (W.J.), and Division of Medicinal Chemistry (Q.L.), School of Pharmacy, Chongqing Medical University, Chongqing, China
J Pharmacol Exp Ther. 2021 Dec;379(3):324-330. doi: 10.1124/jpet.121.000691. Epub 2021 Sep 14.
Etomidate is a potent and rapidly acting anesthetic with high therapeutic index (TI) and superior hemodynamic stability. However, side effect of suppressing adrenocortical function limits its clinical use. To overcome this side effect, we designed a novel etomidate analog, EL-0052, aiming to retain beneficial properties of etomidate and avoid its disadvantage of suppressing adrenocortical steroid synthesis. Results exhibited that EL-0052 enhanced GABA receptors currents with a concentration for EC of 0.98 ± 0.02 μM, which was about three times more potent than etomidate (3.07 ± 1.67 μM). Similar to hypnotic potency of etomidate, EL-0052 exhibited loss of righting reflex with EDs of 1.02 (0.93-1.20) mg/kg in rats and 0.5 (0.45-0.56) mg/kg in dogs. The TI of EL-0052 in rats was 28, which was higher than 22 of etomidate. There was no significant difference in hypnotic onset time, recovery time, and walking time between EL-0052 and etomidate in rats. Both of them had minor effects on mean arterial pressure in dogs. EL-0052 had no significant effect on adrenocortical function in dogs even at a high dose (4.3 × ED), whereas etomidate significantly inhibited corticosteroid secretion. The inhibition of cortisol synthesis assay showed that EL-0052 had a weak inhibition on cortisol biosynthesis in human H259 cells with an IC of 1050 ± 100 nM, which was 2.09 ± 0.27 nM for etomidate. EL-0052 retains the favorable properties of etomidate, including potent hypnotic effect, rapid onset and recovery, stable hemodynamics, and high therapeutic index without suppression of adrenocortical function. SIGNIFICANCE STATEMENT: The novel etomidate analog EL-0052 retains the favorable properties of etomidate without suppressing adrenocortical function and provides a new strategy to optimize the structure of etomidate.
依托咪酯是一种强效、快速起效的麻醉剂，具有较高的治疗指数（TI）和卓越的血液动力学稳定性。然而，其抑制肾上腺皮质功能的副作用限制了其临床应用。为了克服这一副作用，我们设计了一种新型依托咪酯类似物，EL-0052，旨在保留依托咪酯的有益特性，避免其抑制肾上腺皮质类固醇合成的缺点。结果表明，EL-0052增强了 GABA 受体电流，EC 的浓度为 0.98±0.02μM，比依托咪酯（3.07±1.67μM）强约 3 倍。与依托咪酯的催眠效力相似，EL-0052在大鼠中表现出失去翻正反射，ED 为 1.02（0.93-1.20）mg/kg，在犬中为 0.5（0.45-0.56）mg/kg。EL-0052 在大鼠中的 TI 为 28，高于依托咪酯的 22。EL-0052 和依托咪酯在大鼠中的催眠起效时间、恢复时间和行走时间无显著差异。两者在犬中的平均动脉压均无显著影响。EL-0052 即使在高剂量（4.3×ED）下，对犬的肾上腺皮质功能也没有显著影响，而依托咪酯则显著抑制皮质类固醇的分泌。皮质醇合成抑制测定表明，EL-0052 对人 H259 细胞中皮质醇生物合成的抑制作用较弱，IC 为 1050±100nM，依托咪酯为 2.09±0.27nM。EL-0052 保留了依托咪酯的有利特性，包括强效催眠作用、快速起效和恢复、稳定的血液动力学和较高的治疗指数，且不抑制肾上腺皮质功能。意义：新型依托咪酯类似物 EL-0052 保留了依托咪酯的有利特性，且不抑制肾上腺皮质功能，为优化依托咪酯的结构提供了新策略。
