Choi Chulho, Carlo Anthony A, Cronin Ciarán N, Jing Konghua, Kung Daniel W, Liu Jianhua, Lombardo Vincent M, Turco Abigail R, Yin Juxing, Yu Aijia, Wright Stephen W
Medicine Design, Pfizer Worldwide Research, Development and Medical, Eastern Point Road, Groton, Connecticut 06340, United States.
Structural Biology and Protein Sciences, Pfizer Worldwide Research, Development and Medical, La Jolla, California 92121, United States.
ACS Med Chem Lett. 2022 Jan 21;13(2):250-256. doi: 10.1021/acsmedchemlett.1c00634. eCollection 2022 Feb 10.
The metabolic oxidation of drug-like small molecules by aldehyde oxidase (AO) has commonly been mitigated through the incorporation of deuterium at the oxidation site. We report that dimethylformamide dimethyl acetal and related compounds undergo rapid CH to CD isotopic exchange upon exposure to methanol- and similar deuterated alcohols. This isotopic exchange process can be used to synthesize MeNCD(OMe) and has significant implications for the use of MeNCD(OMe) in the synthesis of specifically deuterium-labeled compounds. The application of MeNCD(OMe) to the synthesis of various heterocycles that have been associated with AO metabolism is described, and we report the impact of deuteration on the rate of AO-mediated metabolism.
醛氧化酶（AO）对类药物小分子的代谢氧化通常通过在氧化位点引入氘来减轻。我们报告，二甲基甲酰胺二甲基缩醛及相关化合物在暴露于甲醇和类似的氘代醇时会发生快速的CH到CD同位素交换。这种同位素交换过程可用于合成MeNCD(OMe)，并且对MeNCD(OMe)在特定氘标记化合物合成中的应用具有重要意义。描述了MeNCD(OMe)在各种与AO代谢相关的杂环合成中的应用，并且我们报告了氘代对AO介导的代谢速率的影响。
