The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism.
The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism.
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DOI：
10.1021/acsbiomedchemau.3c00039
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发表时间：
2023-12-20
期刊：
影响因子：
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通讯作者：
Nieman, James A
中科院分区：
文献类型：
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作者：
Arutyunova, Elena;Belovodskiy, Alexandr;Chen, Pu;Khan, Muhammad Bashir;Joyce, Michael;Saffran, Holly;Lu, Jimmy;Turner, Zoe;Bai, Bing;Lamer, Tess;Young, Howard S;Vederas, John C;Tyrrell, D Lorne;Lemieux, M Joanne;Nieman, James A
本研究探讨了Nirmatrelvir的结构改变（如同系化和氘代化）与新合成衍生物的代谢稳定性之间的关系。我们开发了一种可靠的合成方案，对二氘代-尼尔马瑞韦及其同系物与高同位素掺入。Nirmatrelvir主要代谢位点的氘化使其人微粒体稳定性提高3倍，但伴随着次要位点代谢速率的增加。内酰胺环的同源化允许封端基团修饰以降低和离域分子的亲脂性，从而降低次级位点的代谢速率。在人微粒体中，6元内酰胺的氘代效应不如其5元类似物明显，但在小鼠微粒体中，趋势相反。X射线数据显示，内酰胺环的同系化有利于药物的腈弹头与SARS-CoV-2 Mpro的催化硫相互作用的方向，从而改善其结合。观察到新型氘代/同系物衍生物和nirmatrelvir对来自几种关注变体的SARS-CoV-2 Mpro的相当效力和对人半胱氨酸蛋白酶组织蛋白酶B、L和S的选择性。合成的化合物在仓鼠、大鼠和人肝细胞稳定性试验中显示出较大的种间变异性。总体而言，我们的目的是应用合理的方法来改变药物的理化性质，以改善其生化和生物学参数。
This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule’s lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug’s nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 Mpro, improving its binding. Comparable potency against SARS-CoV-2 Mpro from several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters.