超越生物同位体:用富含sp3的三维饱和桥联双环配对对取代苯环对生物转化、代谢稳定性和其他ADME谱的影响。

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Shruti Surendran,Sivashankaran Raju,Naveen Kalyani,Gaurav Saini,Joyson Nandha,Himangshu Bhowmik,Anil Rathod,Shruti Shikha Choubey,Bhuvaneshwaran Anandamoorthy,Sukanta Kumar Sahoo,Yogesh Kumar Gupta,Muthalagu Vetrichelvan,Anuradha Gupta,Salil Desai,Thanga Mariappan,Arvind Mathur,Prakash Ramaseshan Vachaspati,Murugaiah A M Subbaiah
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引用次数: 0

摘要

越来越多地采用三维sp3杂化桥接双环部分作为苯环的饱和生物同分异构体,这标志着现代药物化学的一个引人注目的演变,促进了最近的合成进步。受此启发,我们评估了各种桥接双环体系的代谢稳定性和其他ADME谱,并将它们与单取代苯对应物进行了比较。我们的研究结果表明,这些双环支架增强了代谢稳定性,通过战略性结构修饰,如在桥头堡sp3碳上取代氟或在桥内加入氧原子,进一步显著增强了代谢稳定性。重要的是,代谢物分析显示,这些类似物有效地减轻了活性代谢物的形成,这是含苯基化合物的关键缺陷。值得注意的是,测试的无环配对对显示出总体上比苯基配对对更有利的ADME谱。这些结果共同强调了桥接双环系统在解决药物代谢和ADME特性方面的关键挑战方面的巨大潜力,从而为药物设计提供了有价值的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Beyond Bioisosteres: Impact of Replacing a Benzene Ring with sp3-Rich Three-Dimensional Saturated Bridged Bicyclic Match Pairs on Biotransformation, Metabolic Stability, and Other ADME Profiles.
The increasing adoption of 3D sp3-hybridized bridged bicyclic moieties as saturated bioisosteres of benzene rings signifies a compelling evolution in modern medicinal chemistry, facilitated by recent synthetic advancements. Inspired by this, we evaluated the metabolic stability and other ADME profiles of various bridged bicyclic systems, comparing them to a monosubstituted benzene counterpart. Our findings indicate that these bicyclic scaffolds enhance metabolic stability, with further notable enhancements achieved by strategic structural modifications, such as fluorine substitution at the bridgehead sp3 carbon or incorporation of an oxygen atom within the bridge. Importantly, metabolite profiling revealed that these analogues effectively mitigate the formation of reactive metabolites, a critical liability of phenyl-containing compounds. Notably, the tested oxabicyclic match pairs demonstrated overall more favorable ADME profiles than the phenyl counterpart. These results collectively underscore the promising potential of bridged bicyclic systems to address key challenges in drug metabolism and ADME properties, thereby offering valuable insights for drug design.
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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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