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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Posted on 2021-01-11 - 18:36
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.
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Oukoloff, Killian; Nzou, Goodwell; Varricchio, Carmine; Lucero, Bobby; Alle, Thibault; Kovalevich, Jane; et al. (2021). Evaluation of the Structure–Activity Relationship
of Microtubule-Targeting 1,2,4-Triazolo[1,5‑a]pyrimidines Identifies New Candidates for Neurodegenerative Tauopathies. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.0c01605