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新型丙氨酰胺衍生物的开发具有抗惊厥活性和良好的动物模型安全性特征。

Development of Novel Alaninamide Derivatives with Anticonvulsant Activity and Favorable Safety Profiles in Animal Models.

机构信息

Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.

Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.

出版信息

Int J Mol Sci. 2024 Sep 12;25(18):9861. doi: 10.3390/ijms25189861.

Abstract

In our current study, we developed a focused series of original ((benzyloxy)benzyl)propanamide derivatives that demonstrated potent activity across in vivo mouse seizure models, specifically, maximal electroshock (MES) and 6 Hz (32 mA) seizures. Among these derivatives, compound emerged as a lead molecule, exhibiting robust protection following intraperitoneal (i.p.) injection, as follows: ED = 48.0 mg/kg in the MES test, ED = 45.2 mg/kg in the 6 Hz (32 mA) test, and ED = 201.3 mg/kg in the 6 Hz (44 mA) model. Additionally, compound displayed low potential for inducing motor impairment in the rotarod test (TD > 300 mg/kg), indicating a potentially favorable therapeutic window. In vitro toxicity assays further supported its promising safety profile. We also attempted to identify a plausible mechanism of action of compound by applying both binding and functional in vitro studies. Overall, the data obtained for this lead molecule justifies the more comprehensive preclinical development of compound as a candidate for a potentially broad-spectrum and safe anticonvulsant.

摘要

在我们目前的研究中,我们开发了一系列重点的((苯氧基)苄基)丙酰胺衍生物,这些衍生物在体内小鼠癫痫模型中表现出了强大的活性,特别是最大电休克 (MES) 和 6 Hz (32 mA) 癫痫发作。在这些衍生物中,化合物 表现出了作为先导分子的潜力,在腹腔注射后表现出了强大的保护作用,如下所示:在 MES 测试中的 ED = 48.0 mg/kg,在 6 Hz (32 mA) 测试中的 ED = 45.2 mg/kg,在 6 Hz (44 mA) 模型中的 ED = 201.3 mg/kg。此外,化合物 在旋转棒测试中显示出低诱导运动障碍的潜力(TD > 300 mg/kg),表明其具有潜在的有利治疗窗口。体外毒性试验进一步支持了其良好的安全性概况。我们还尝试通过应用结合和功能体外研究来确定化合物 的可能作用机制。总的来说,获得的数据证明了化合物 作为一种潜在的广谱和安全抗惊厥候选药物进行更全面的临床前开发是合理的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/949d/11432405/898ccf3b0bac/ijms-25-09861-g001.jpg

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