{"title":"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。","authors":"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","doi":"10.1021/acs.jmedchem.5c01879","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"99 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"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\",\"doi\":\"10.1021/acs.jmedchem.5c01879\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"99 1\",\"pages\":\"\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.5c01879\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.5c01879","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
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.
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.