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Evaluation of the Structure-Activity Relationship of Microtubule-Targeting 1,2,4-Triazolo[1,5-a]pyrimidines Identifies New Candidates for Neurodegenerative Tauopathies.
Oukoloff, Killian; Nzou, Goodwell; Varricchio, Carmine; Lucero, Bobby; Alle, Thibault; Kovalevich, Jane; Monti, Ludovica; Cornec, Anne-Sophie; Yao, Yuemang; James, Michael J; Trojanowski, John Q; Lee, Virginia M-Y; Smith, Amos B; Brancale, Andrea; Brunden, Kurt R; Ballatore, Carlo.
Afiliación
  • Oukoloff K; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
  • Nzou G; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
  • Varricchio C; Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF103NB, U.K.
  • Lucero B; Department of Chemistry & Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
  • Alle T; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
  • Kovalevich J; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
  • Monti L; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
  • Cornec AS; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
  • Yao Y; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
  • James MJ; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
  • Trojanowski JQ; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
  • Lee VM; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
  • Smith AB; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
  • Brancale A; Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF103NB, U.K.
  • Brunden KR; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, United States.
  • Ballatore C; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
J Med Chem ; 64(2): 1073-1102, 2021 01 28.
Article en En | MEDLINE | ID: mdl-33411523
Studies in tau and Aß plaque transgenic mouse models demonstrated that brain-penetrant microtubule (MT)-stabilizing compounds, including the 1,2,4-triazolo[1,5-a]pyrimidines, hold promise as candidate treatments for Alzheimer's disease and related neurodegenerative tauopathies. Triazolopyrimidines have already been investigated as anticancer agents; however, the antimitotic activity of these compounds does not always correlate with stabilization of MTs in cells. Indeed, previous studies from our laboratories identified a critical role for the fragment linked at C6 in determining whether triazolopyrimidines promote MT stabilization or, conversely, disrupt MT integrity in cells. To further elucidate the structure-activity relationship (SAR) and to identify potentially improved MT-stabilizing candidates for neurodegenerative disease, a comprehensive set of 68 triazolopyrimidine congeners bearing structural modifications at C6 and/or C7 was designed, synthesized, and evaluated. These studies expand upon prior understanding of triazolopyrimidine SAR and enabled the identification of novel analogues that, relative to the existing lead, exhibit improved physicochemical properties, MT-stabilizing activity, and pharmacokinetics.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Triazoles / Enfermedades Neurodegenerativas / Tauopatías / Microtúbulos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Triazoles / Enfermedades Neurodegenerativas / Tauopatías / Microtúbulos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos