Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G1 1XQ, UK.
Molecules. 2022 Feb 6;27(3):1090. doi: 10.3390/molecules27031090.
The treatment of seizure disorders with currently available pharmacotherapeutic agents is not optimal due to the failure of some patients to respond, coupled with occurrences of side effects. There is therefore a need for research into the development of new chemical entities as potential anticonvulsant agents, which are different structurally from the existing class of drugs. We recently identified a novel triazolyl-oxazolidinone derivative, PH-192, as a potential anticonvulsant agent. PH-192 demonstrated protection comparable to phenytoin against both chemically- and electrically-induced seizures in rodents with little or no central nervous system side effects. However, PH-192 did not exhibit protection beyond 30 min; therefore, we decide to investigate a stability-indicating assay of PH-192 in plasma and other solutions. A reliable and validated analytical method was developed to investigate the stability of PH-192 for 90 min in human plasma, acidic, basic, and oxidative conditions, using a Waters Acquity ultra high-performance liquid chromatography (UHPLC) system with a quaternary Solvent Manager (H-Class). A simple extraction method indicated that PH-192 was stable in human plasma after 90 min at 37 °C, with more than 90% successfully recovered. Moreover, stress stability studies were performed, and degradants were identified using LC-QToF-MS under acidic, basic, and oxidative simulated conditions.
由于一些患者没有反应，加上出现副作用，目前可用的药物治疗癫痫发作的效果并不理想。因此，有必要研究开发新的化学实体作为潜在的抗惊厥药物，这些药物在结构上与现有药物类别不同。我们最近发现一种新型三唑基恶唑烷酮衍生物 PH-192，作为一种有潜力的抗惊厥药物。PH-192在啮齿动物中对化学和电诱导的癫痫发作具有与苯妥英相当的保护作用，几乎没有或没有中枢神经系统副作用。然而，PH-192 的保护作用没有超过 30 分钟；因此，我们决定研究 PH-192 在血浆和其他溶液中的稳定性指示测定法。开发了一种可靠和验证的分析方法，用于在人血浆、酸性、碱性和氧化条件下在 90 分钟内研究 PH-192 的稳定性，使用带有四元溶剂管理器（H-Class）的 Waters Acquity 超高效液相色谱（UHPLC）系统。简单的提取方法表明，PH-192 在 37°C 下 90 分钟后在人血浆中稳定，超过 90%成功回收。此外，还进行了应激稳定性研究，并在酸性、碱性和氧化模拟条件下使用 LC-QToF-MS 鉴定了降解产物。
