دورية أكاديمية
Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity.
| العنوان: | Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity. |
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| المؤلفون: | Verdonck S; Medicinal Chemistry, Rega Institute for Medical Research , KU Leuven , Herestraat 49-bus 1041 , 3000 Leuven , Belgium., Pu SY; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology , Stanford University School of Medicine , Stanford , California 94305 , United States., Sorrell FJ; Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI) and Structural Genomics Consortium (SGC) , University of Oxford , Old Road Campus, Roosevelt Drive , Oxford OX3 7DQ , U.K., Elkins JM; Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI) and Structural Genomics Consortium (SGC) , University of Oxford , Old Road Campus, Roosevelt Drive , Oxford OX3 7DQ , U.K.; Structural Genomics Consortium , Universidade Estadual de Campinas , Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello, 550 , Barão Geraldo, Campinas , São Paulo 13083-886 , Brazil., Froeyen M; Medicinal Chemistry, Rega Institute for Medical Research , KU Leuven , Herestraat 49-bus 1041 , 3000 Leuven , Belgium., Gao LJ; Medicinal Chemistry, Rega Institute for Medical Research , KU Leuven , Herestraat 49-bus 1041 , 3000 Leuven , Belgium., Prugar LI; US Army Medical Research Institute of Infectious Diseases , Viral Immunology Branch , Fort Detrick , Maryland 21702 , United States., Dorosky DE; US Army Medical Research Institute of Infectious Diseases , Viral Immunology Branch , Fort Detrick , Maryland 21702 , United States., Brannan JM; US Army Medical Research Institute of Infectious Diseases , Viral Immunology Branch , Fort Detrick , Maryland 21702 , United States., Barouch-Bentov R; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology , Stanford University School of Medicine , Stanford , California 94305 , United States., Knapp S; Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI) and Structural Genomics Consortium (SGC) , University of Oxford , Old Road Campus, Roosevelt Drive , Oxford OX3 7DQ , U.K.; Institute for Pharmaceutical Chemistry, Buchmann Institute for Life Sciences Campus Riedbeerg , Goethe-University Frankfurt , 60438 Frankfurt am Main , Germany., Dye JM; US Army Medical Research Institute of Infectious Diseases , Viral Immunology Branch , Fort Detrick , Maryland 21702 , United States., Herdewijn P; Medicinal Chemistry, Rega Institute for Medical Research , KU Leuven , Herestraat 49-bus 1041 , 3000 Leuven , Belgium., Einav S; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology , Stanford University School of Medicine , Stanford , California 94305 , United States., De Jonghe S; Medicinal Chemistry, Rega Institute for Medical Research , KU Leuven , Herestraat 49-bus 1041 , 3000 Leuven , Belgium. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2019 Jun 27; Vol. 62 (12), pp. 5810-5831. Date of Electronic Publication: 2019 Jun 12. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Antiviral Agents/*chemical synthesis , Antiviral Agents/*pharmacology , Protein Kinase Inhibitors/*chemical synthesis , Protein Kinase Inhibitors/*pharmacology , Protein Serine-Threonine Kinases/*antagonists & inhibitors , Pyridines/*chemical synthesis , Pyridines/*pharmacology, Antiviral Agents/chemistry ; Antiviral Agents/metabolism ; Cell Line ; Chemistry Techniques, Synthetic ; Humans ; Molecular Docking Simulation ; Protein Conformation ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/metabolism ; Protein Serine-Threonine Kinases/chemistry ; Protein Serine-Threonine Kinases/metabolism ; Pyridines/chemistry ; Pyridines/metabolism ; Structure-Activity Relationship |
| مستخلص: | There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3- b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy. |
| References: | ACS Med Chem Lett. 2016 Apr 20;7(6):629-34. (PMID: 27326339) Structure. 2016 Mar 1;24(3):401-11. (PMID: 26853940) J Indian Med Assoc. 1991 Jun;89(6):152-3. (PMID: 1748784) Nat Biotechnol. 2005 Mar;23(3):329-36. (PMID: 15711537) Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42. (PMID: 21460441) Org Biomol Chem. 2017 Jan 4;15(2):373-378. (PMID: 27910980) J Clin Invest. 2017 Apr 3;127(4):1338-1352. (PMID: 28240606) J Org Chem. 2016 Jul 1;81(13):5636-48. (PMID: 27303950) J Virol. 2003 Sep;77(18):9733-7. (PMID: 12941881) J Comput Chem. 2004 Oct;25(13):1605-12. (PMID: 15264254) Virology. 2010 Jan 20;396(2):305-15. (PMID: 19913272) Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55. (PMID: 15299926) J Virol. 2015 Apr;89(8):4387-404. (PMID: 25653444) J Comput Chem. 2009 Dec;30(16):2785-91. (PMID: 19399780) Antimicrob Agents Chemother. 2013 Jan;57(1):15-25. (PMID: 23070172) Expert Opin Drug Discov. 2015 May;10(5):449-61. (PMID: 25835573) Clin Epidemiol. 2013 Aug 20;5:299-309. (PMID: 23990732) J Virol. 2013 Apr;87(8):4609-22. (PMID: 23408612) J Comput Chem. 2010 Jan 30;31(2):455-61. (PMID: 19499576) Antiviral Res. 2018 Jul;155:67-75. (PMID: 29753658) Nat Biotechnol. 2008 Jan;26(1):127-32. (PMID: 18183025) Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002) Angew Chem Int Ed Engl. 2014 Oct 13;53(42):11140-5. (PMID: 25131311) J Pharmacol Exp Ther. 2016 Sep;358(3):371-86. (PMID: 27411717) Angew Chem Int Ed Engl. 2013 Sep 16;52(38):10093-6. (PMID: 23897626) MBio. 2018 Mar 13;9(2):. (PMID: 29535204) Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702) Curr Treat Options Infect Dis. 2017;9(3):299-317. (PMID: 28890666) Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32. (PMID: 20124692) Science. 2015 Apr 17;348(6232):282-3. (PMID: 25883340) J Med Chem. 2013 Dec 12;56(23):9569-85. (PMID: 24188002) Bioorg Med Chem Lett. 2010 Jul 15;20(14):4273-8. (PMID: 20621733) Chem Biol. 2011 Jul 29;18(7):891-906. (PMID: 21802010) J Virol. 2010 May;84(9):4845-50. (PMID: 20164230) Antiviral Res. 2008 Oct;80(1):11-22. (PMID: 18585795) J Med Chem. 2014 Sep 25;57(18):7624-43. (PMID: 25178155) J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674. (PMID: 19461840) Wkly Epidemiol Rec. 2016 Jul 29;91(30):349-64. (PMID: 27476189) J Cell Biol. 2011 Dec 26;195(7):1071-82. (PMID: 22123832) Bioorg Med Chem. 2007 Nov 1;15(21):6782-95. (PMID: 17723306) PLoS Pathog. 2012;8(8):e1002845. (PMID: 22916011) J Med Chem. 2008 Dec 25;51(24):7898-914. (PMID: 19035792) |
| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; UL1 TR000093 United States TR NCATS NIH HHS; 106169/ZZ14/Z United Kingdom WT_ Wellcome Trust |
| المشرفين على المادة: | 0 (Antiviral Agents) 0 (Protein Kinase Inhibitors) 0 (Pyridines) EC 2.7.11.1 (AAK1 protein, human) EC 2.7.11.1 (Protein Serine-Threonine Kinases) |
| تواريخ الأحداث: | Date Created: 20190529 Date Completed: 20200528 Latest Revision: 20211204 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC6825517 |
| DOI: | 10.1021/acs.jmedchem.9b00136 |
| PMID: | 31136173 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.9b00136 |