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Quantification of Linrodostat and its metabolites: Overcoming bioanalytical challenges in support of a discovery Indoleamine 2,3 dioxygenase program
Journal of Chromatography B ( IF 2.8 ) Pub Date : 2022-06-28 , DOI: 10.1016/j.jchromb.2022.123305
Lorell N Discenza 1 , Aaron Balog 2 , Christine Huang 1 , Robin Moore 1 , Asoka Ranasinghe 1 , Tai-An Lin 2 , Celia D'Arienzo 1 , Timothy V Olah 1
Affiliation  

BMS-986205 (Linrodostat) is a small molecule inhibitor of Indoleamine 2, 3 dioxygenase (IDO) that is currently being evaluated in clinical trials for the oral treatment of advanced cancer. Initially, there were concerns regarding possible toxicity following administration, since BMS-986205 undergoes metabolism to form 4-chloroaniline. However, it was later determined that the downstream metabolites of 4-chloroaniline might be a greater concern. To evaluate the potential toxicity of these metabolites, a sensitive LC-MS/MS analytical method was needed to quantify both the parent compound and multiple metabolites. This presented a challenge since the method required the analysis of multiple analytes while still retaining the analytical sensitivity required to support studies. By utilizing a multi-function analytical method, we were able to quantify the necessary analytes using a complex LC-MS/MS-based method including the application of both negative and positive electrospray ionization.



中文翻译:

Linrodostat 及其代谢物的量化:克服生物分析挑战以支持发现吲哚胺 2,3 双加氧酶计划

BMS-986205 (Linrodostat) 是一种吲哚胺 2, 3 双加氧酶 (IDO) 的小分子抑制剂,目前正在临床试验中对晚期癌症的口服治疗进行评估。最初,有人担心给药后可能的毒性,因为 BMS-986205 会代谢形成 4-氯苯胺。然而,后来确定 4-氯苯胺的下游代谢物可能是一个更大的问题。为了评估这些代谢物的潜在毒性,需要一种灵敏的 LC-MS/MS 分析方法来量化母体化合物和多种代谢物。这提出了一个挑战,因为该方法需要分析多种分析物,同时仍保持支持研究所需的分析灵敏度。通过利用多功能分析方法,

更新日期:2022-06-28
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