Brain penetrant, microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines have produced promising results in different mouse models of Alzheimer’s disease (AD) and tauopathy, suggesting that compounds from this class may be considered as candidate therapeutics for AD and other neurodegenerative diseases. However, depending on the substitution pattern, these compounds can elicit very different cellular responses by either promoting MT stabilization or, conversely, disrupting MT integrity in cells. To further elucidate the structure-activity relationships and to identify potentially improved MT-stabilizing candidates for neurodegenerative disease, a comprehensive set of triazolopyrimidine congeners (&gt;65 compounds) bearing structural modifications at the C6 and/or C7 positions was designed, synthesized and evaluated. The results of these studies enabled both the development of predictive QSAR models as well as the design of congeners (e.g., CNDR-51997, Figure 1) exhibiting improved drug-like properties and MT-stabilizing activity. Moreover, the most important stereoelectronic characteristics of the C6 and C7 fragments were defined that result in relatively potent MT-stabilizing activity in cells without a concurrent reduction in cellular tubulin levels.

Evaluation of structure-activity relationships of microtubule (MT)-targeting 1,2,4-triazolo[1,5-a]pyrimidines identifies new candidates for neurodegenerative diseases

ACS Spring Meeting 2021

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