| 描述 |
(1S,2R)-阿利卡司他((1S、2R)-ABT-957)是一种口服活性选择性人类钙蛋白酶抑制剂1和2,用于潜在的阿尔茨海默病(AD)[1]。(1S,2R)-阿利卡司他减轻羰基还原的代谢责任,并以395 nM的IC50值抑制calpain 1[2]。
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| 相关类别 |
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| 靶点 |
IC50: 395 nM (human calpain 1)[1]
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| 体外研究 |
(1S,2R)-阿利卡司他抑制中枢神经系统渗透浓度不足,以获得药效学效应[1]。钙蛋白酶1(µ-Calpain)和2(m-Calpain),分别以钙依赖性方式表达,其各自激活所需的µ-摩尔或m-摩尔钙浓度。(1S,2R)-阿利卡司他(化合物22)(100nM)可防止Aβ低聚物诱导的大鼠突触传递缺陷[2]。(1S,2R)-阿利卡司他(化合物22)(385nM)在预防NMDA诱导的神经变性和A诱导的突触功能障碍方面具有双重功效[2]。(1S,2R)-阿利卡司他(9-21 nM)的脑脊液浓度未达到钙蛋白酶抑制的IC50,在广泛人群研究中未显示剂量限制毒性(DLT)[3]。
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| 体内研究 |
(1S,2R)-阿利卡司他(化合物22)(iv或po；1-3 mg/kg)在小鼠、大鼠和狗中显示中等平均血浆清除值(CLp)(0.13-1.04 L/hr.kg),而在猴中显示较高(1.98 L/hr.kg)。小鼠、狗和猴子的平均稳态分布体积值(Vss)中等(0.64-1.8 L/kg),但大鼠(3.4 L/kg)较高。狗的血浆消除半衰期(t1/2)最短(1.7小时),其次是猴的2.3小时,小鼠和大鼠的约6.0小时。口服生物利用度(F)值在小鼠、大鼠和狗中较高(>80%),而在猴子中为中等(14%)[2]。
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| 参考文献 |
[1]. Lon HK, et al. Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of Alicapistat, a Selective Inhibitor of Human Calpains 1 and 2 for the Treatment of Alzheimer Disease: An Overview of Phase 1 Studies. Clin Pharmacol Drug Dev. 2019 Apr. 8(3):290-303. [2]. Jantos K, et al. Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability. Bioorg Med Chem Lett. 2019 Aug 1. 29(15):1968-1973. [3]. Jastaniah A, Gaisina IN, Knopp RC, Thatcher GRJ. Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents. ChemMedChem. 2020 Dec 3. 15(23):2280-2285.
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