Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability,Journal of Medicinal Chemistry

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Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-22 , DOI: 10.1021/acs.jmedchem.3c01876
Shenghua Gao _{1,

2} , Letian Song ₁ , Katharina Sylvester ₃ , Beatrice Mercorelli ₄ , Arianna Loregian ₄ , Karoly Toth ₅ , Renato H Weiße ₆ , Abibe Useini ₆ , Norbert Sträter ₆ , Mianling Yang ₁ , Bing Ye ₁ , Ann E Tollefson ₅ , Christa E Müller ₃ , Xinyong Liu ₁ , Peng Zhan ₁

Affiliation

The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and future coronaviruses. Here, we present the discovery of potent nonpeptide main protease (M^pro) inhibitors with prominent antiviral activity and improved pharmacokinetic properties. Three series of 1,2,4-trisubstituted piperazine derivatives were designed and synthesized, and the optimal GC-78-HCl demonstrated high enzyme–inhibitory potency (IC₅₀ = 0.19 μM) and exhibited excellent antiviral activity (EC₅₀ = 0.40 μM), reaching the same level as Nirmatrelvir (EC₅₀ = 0.38 μM). Additionally, GC-78-HCl displayed potent antiviral activities against various SARS-CoV-2 variants as well as HCoV-OC43 and HCoV-229E, indicating its potential broad-spectrum anticoronaviral activity. Notably, the pharmacokinetic properties of GC-78-HCl were somewhat enhanced compared to those of the lead compound. Furthermore, the cocrystal and molecular docking elucidated the mechanism of action. In conclusion, we discovered a novel nonpeptidic M^pro inhibitor with promising antiviral activity and a favorable pharmacokinetic profile.

中文翻译：

作为非共价严重急性呼吸综合征冠状病毒2主要蛋白酶抑制剂的三取代哌嗪衍生物的设计、合成和生物学评价，具有改善的抗病毒活性和良好的成药性

SARS-CoV-2 的持续传播需要开发更多有效的抗病毒药物，以对抗当前高度传染性的变种和未来的冠状病毒。在这里，我们发现了有效的非肽主要蛋白酶 (M ^pro ) 抑制剂，具有显着的抗病毒活性和改善的药代动力学特性。设计并合成了三个系列的1,2,4-三取代哌嗪衍生物，最优的GC-78-HCl表现出较高的酶抑制效力（IC ₅₀ = 0.19 μM）并表现出优异的抗病毒活性（EC ₅₀ = 0.40 μM），达到与 Nirmatrelvir 相同的水平 (EC ₅₀ = 0.38 μM)。此外， GC-78-HCl对各种 SARS-CoV-2 变体以及 HCoV-OC43 和 HCoV-229E 显示出有效的抗病毒活性，表明其潜在的广谱抗冠状病毒活性。值得注意的是，与先导化合物相比， GC-78-HCl的药代动力学特性有所增强。此外，共晶和分子对接阐明了作用机制。总之，我们发现了一种新型非肽 M ^pro抑制剂，具有良好的抗病毒活性和良好的药代动力学特征。

更新日期：2023-11-22

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