UC San Diego

A subset of neurodegenerative diseases known as tauopathies, of which Alzheimer’s disease (AD) is the most prominent example, are defined by the presence of proteinaceous inclusions comprised of hyperphosphorylated tau protein within neurons. Tau has been shown to provide stability to microtubules (MTs), key constituents of the cytoskeleton that are involved in a variety of cellular functions, including cell communication and transport. Tau hyperphosphorylation and mutation causes it to detach from MTs and causes them to destabilize leading to axonal transport deficits and, ultimately, neuronal loss. A possible strategy of therapeutic intervention calls for the development of brain penetrant MT-stabilizing agents that could compensate for the loss of tau function in neurons. Through a screen of non-naturally occurring small molecules, a few selected classes of molecules were found to have advantages over MT stabilizing natural products, in terms of synthetic accessibility and drug like physicochemical properties. Preliminary evaluation and SAR of those selected classes led to the identification of a preferred subset of triazolopyrimidines which were shown to be brain penetrant, orally bioavailable, and possess other favorable pharmacokinetic properties. The initial cellular assessment of triazolopyrimidines (TPDs) found that depending on the substitution pattern TPDs can either preserve or disrupt MT integrity in cells. Presented here are the design, synthesis and in vitro evaluation of a set of triazolopyrimidine congeners bearing a range of structural modifications at position 6 and/or 7. These studies complement and expand prior SAR studies and characterize the role that substituents of the triazolopyrimidine scaffold can have in determining MT-stabilizing activity.