Susan H. Davis, Michael Mathieson, Kirsteen I. Buchanan, Alice Dawson, Alasdair Smith, Mattia Cocco, Fabio K. Tamaki, John M. Post, Beatriz Baragaña, Chimed Jansen, Michael Kiczun, Fabio Zuccotto, Gavin Wood, Paul Scullion, Peter C. Ray, Ola Epemolu, Eva Maria Lopez-Román, Laura Guijarro López, Curtis A. Engelhart, Jia Kim, Paula A. Pino, Dirk Schnappinger, Kevin D. Read, Lourdes Encinas, Robert H. Bates, Paul G. Wyatt, Simon R. Green and Laura A. T. Cleghorn*,
{"title":"用于治疗肺结核的赖氨酸tRNA合成酶抑制剂的设计与开发。","authors":"Susan H. Davis, Michael Mathieson, Kirsteen I. Buchanan, Alice Dawson, Alasdair Smith, Mattia Cocco, Fabio K. Tamaki, John M. Post, Beatriz Baragaña, Chimed Jansen, Michael Kiczun, Fabio Zuccotto, Gavin Wood, Paul Scullion, Peter C. Ray, Ola Epemolu, Eva Maria Lopez-Román, Laura Guijarro López, Curtis A. Engelhart, Jia Kim, Paula A. Pino, Dirk Schnappinger, Kevin D. Read, Lourdes Encinas, Robert H. Bates, Paul G. Wyatt, Simon R. Green and Laura A. T. Cleghorn*, ","doi":"10.1021/acs.jmedchem.5c01331","DOIUrl":null,"url":null,"abstract":"<p >There is currently a public health crisis due to the rise of multidrug-resistant tuberculosis cases, as well as the rise in the number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of <b>49</b>, a preclinical candidate that acted through inhibition of the <i>Mycobacterium tuberculosis</i> lysyl tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimized lead. The work was guided by the first crystal structures of <i>M. tuberculosis</i> LysRS. The physicochemical and pharmacokinetic properties were optimized to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 15","pages":"16459–16482"},"PeriodicalIF":6.8000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5c01331","citationCount":"0","resultStr":"{\"title\":\"Design and Development of Lysyl tRNA Synthetase Inhibitors, for the Treatment of Tuberculosis\",\"authors\":\"Susan H. Davis, Michael Mathieson, Kirsteen I. Buchanan, Alice Dawson, Alasdair Smith, Mattia Cocco, Fabio K. Tamaki, John M. Post, Beatriz Baragaña, Chimed Jansen, Michael Kiczun, Fabio Zuccotto, Gavin Wood, Paul Scullion, Peter C. Ray, Ola Epemolu, Eva Maria Lopez-Román, Laura Guijarro López, Curtis A. Engelhart, Jia Kim, Paula A. Pino, Dirk Schnappinger, Kevin D. Read, Lourdes Encinas, Robert H. Bates, Paul G. Wyatt, Simon R. Green and Laura A. T. Cleghorn*, \",\"doi\":\"10.1021/acs.jmedchem.5c01331\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >There is currently a public health crisis due to the rise of multidrug-resistant tuberculosis cases, as well as the rise in the number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of <b>49</b>, a preclinical candidate that acted through inhibition of the <i>Mycobacterium tuberculosis</i> lysyl tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimized lead. The work was guided by the first crystal structures of <i>M. tuberculosis</i> LysRS. The physicochemical and pharmacokinetic properties were optimized to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"68 15\",\"pages\":\"16459–16482\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5c01331\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01331\",\"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://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01331","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Design and Development of Lysyl tRNA Synthetase Inhibitors, for the Treatment of Tuberculosis
There is currently a public health crisis due to the rise of multidrug-resistant tuberculosis cases, as well as the rise in the number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of 49, a preclinical candidate that acted through inhibition of the Mycobacterium tuberculosis lysyl tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimized lead. The work was guided by the first crystal structures of M. tuberculosis LysRS. The physicochemical and pharmacokinetic properties were optimized to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.
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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