- Evaluation of the Structure-Activity Relationship of Microtubule-Targeting 1,2,4-Triazolo[1,5- a]pyrimidines Identifies New Candidates for Neurodegenerative Tauopathies
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Studies in tau and Aβ 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.
- 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
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p. 1073 - 1102
(2021/02/03)
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- Brain-penetrant, orally bioavailable microtubule-stabilizing small molecules are potential candidate therapeutics for Alzheimer's disease and related tauopathies
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Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer's disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD p
- Lou, Kevin,Yao, Yuemang,Hoye, Adam T.,James, Michael J.,Cornec, Anne-Sophie,Hyde, Edward,Gay, Bryant,Lee, Virginia M.-Y.,Trojanowski, John Q.,Smith, Amos B.,Brunden, Kurt R.,Ballatore, Carlo
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p. 6116 - 6127
(2014/08/18)
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- HETEROCYCLIC COMPOUNDS AND THEIR USE FOR THE TREATMENT OF NEURODEGENERATIVE TAUOPATHIES
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The present invention is directed to triazolopyrimidine, phenylpyrimidine, pyridopyridazine, and pyridotriazine compounds and their use in the treatment of neurodegenerative disorders.
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Paragraph 0098; 0100
(2014/04/04)
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- Synthesis and SAR of [1,2,4]triazolo[1,5-a]pyrimidines, a class of anticancer agents with a unique mechanism of tubulin inhibition
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The synthesis and SAR of a series of triazolopyrimidines as anticancer agents are described. Treatment of 5-chloro-6-(trifluorophenyl)-N-fluoroalkyl[1, 2,4]triazolo[1,5-a]pyrimidin-7-amine with an alcohol, a thiol, or an alkylamine provided the corresponding final compounds. A clear SAR requirement has been established for optimal activity. A (1S)-2,2,2-trifluoro-1-methylethylamino group or an achiral 2,2,2-trifluoroethylamino group is required at the 5-position to achieve high potency. On the phenyl ring, both fluoro atoms, at the positions ortho to the triazolopyrimidine core, are needed for optimal activity. At the position para to the triazolopyrimidine core, on the phenyl ring, the best activity is achieved with an oxygen linkage followed by a three-methylene unit, and an alkylamino or a hydroxy group. The mechanism of action for this series of triazolopyrimidines was shown to be unique in that they promoted tubulin polymerization in vitro, but did not bind competitively with paclitaxel. Instead, they inhibit the binding of vincas to tubulin. Selected compounds were studied further, and it was shown that these compounds were able to overcome resistance attributed to several multidrug resistance transporter proteins. Lead compounds were shown to inhibit tumor growth in several nude mouse xenograft models, with high potency and efficacy, when dosed either orally or intravenously.
- Zhang, Nan,Ayral-Kaloustian, Semiramis,Nguyen, Thai,Afragola, Jay,Hernandez, Richard,Lucas, Judy,Gibbons, James,Beyer, Carl
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p. 319 - 327
(2007/10/03)
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- Process for the preparation of tubulin inhibitors
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The present invention provides a process for the preparation of 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt and as a hydrated salt having the structural formula (I) wherein: R1 is CF3 or C2F5/su
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Page/Page column 8
(2010/02/11)
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- 6-[(SUBSTITUTED)PHENYL]TRIAZOLOPYRIMIDINES AS ANTICANCER AGENTS
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This invention relates to certain 6-[(substituted)phenyl]triazolopyrimidine compounds or pharmaceutically acceptable salts thereof, and compositions containing said compounds or pharmaceutically acceptable salts thereof, wherein said compounds are anti-cancer agents useful for the treatment of cancer in mammals. This invention further relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal and further provides a method for the treatment or prevention of cancerous tumors that express multiple drug resistance (MDR) or are resistant because of MDR, in a mammal in need thereof which method comprises administering to said mammal an effective amount of said compounds or pharmaceutically acceptable salts thereof. The present invention relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal in need thereof by promotion of microtubule polymerization which comprises administering to said mammal an effective amount of said compounds and pharmaceutically acceptable salts thereof.
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Page/Page column 71-72
(2008/06/13)
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