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. and Ballatore, Carlo 2021. Evaluation of the structure-activity relationship of microtubule-targeting 1,2,4-Triazolo[1,5-a]pyrimidines identifies new candidates for neurodegenerative tauopathies. Journal of Medicinal Chemistry 64 (2) , pp. 1073-1102. 10.1021/acs.jmedchem.0c01605 Item availability restricted.

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	11 January 2021
Date of Acceptance:	11 December 2020
Last Modified:	23 Feb 2021 13:11
URI:	http://orca.cf.ac.uk/id/eprint/137543

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