尼马特瑞韦内酰胺环的氘化和同源化对其生化特性和氧化代谢的影响

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-11-15 DOI:10.1021/acsbiomedchemau.3c00039
Elena Arutyunova, Alexandr Belovodskiy*, Pu Chen, Muhammad Bashir Khan, Michael Joyce, Holly Saffran, Jimmy Lu, Zoe Turner, Bing Bai, Tess Lamer, Howard S. Young, John C. Vederas, D. Lorne Tyrrell, M. Joanne Lemieux* and James A. Nieman, 
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摘要

本研究探讨了nirmatrelvir的同源性和氘化等结构变化与新合成衍生物代谢稳定性之间的关系。我们开发了一个可靠的合成方案,以dideutero-nirmatrelvir及其同源类似物与高同位素掺入。尼马特利韦主要代谢位点的氘化使其人微粒体稳定性提高了3倍,但伴随的是次要代谢位点的代谢率增加。内酰胺环的同源性允许封盖基团修饰降低和脱域分子的亲脂性,降低二级位点的代谢率。在人微粒体中,氘化对6元内酰胺的影响不如对其5元类似物的影响明显,但在小鼠微粒体中,趋势是相反的。x射线数据显示,内酰胺环的同源性有利于药物的腈战斗部与SARS-CoV-2 Mpro的催化硫相互作用的取向,从而改善其结合。观察到新型氘化/同源衍生物和nirmatrelvir对几种关注变体的SARS-CoV-2 Mpro具有相当的效力,并且对人半胱氨酸蛋白酶组织蛋白酶B、L和S具有选择性。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很大的种间变异性。总的来说,我们的目标是应用合理的方法来改变药物的物理化学性质,以改善其生化和生物学参数。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism

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.

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来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
自引率
0.00%
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0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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