One of the hallmarks of the early stages of Alzheimer’s disease (AD) is mitochondrial dysfunction. This is due, in part, to the interaction between amyloid beta-protein (Aβ), the protein implicated in AD pathology, and amyloid-binding alcohol dehydrogenase (ABAD). The mitochondrial enzyme ABAD is a vital energy regulator in the mitochondria containing a Rossmann fold that acts to oxidize alcohols and reduce aldehydes. Further, ABAD oxidizes 3-hydroxyacyl-CoAs in the β-oxidation cycle, 3α-adiol to 5α-dihydrotestosterone in androgen metabolism and more importantly estradiol to estrone in estrogen metabolism. Estradiol levels intracellularly are an essential determinant of neuronal survival. One of the significant roles of ABAD is to maintain the balance of estradiol/estrone in neurons, Aβ-ABAD interaction disrupts this balance and leads to a reduction in the levels of estradiol. Subsequently, leading to an increase in reactive oxygen species levels, DNA fragmentation, and apoptosis. Thus, ABAD represents a novel target for the development of pharmacological inhibitors to treat AD. Prior studies have identified the most potent inhibitor to date, AG18051, (IC50= 92 nM), containing a pyrazolo[3,4-d]pyrimidine-4(1H)- thione backbone. The compound binds in the active-site cavity of the enzyme and forms a covalent adduct with the NAD+ cofactor. Despite its promising activity, AG18051 has not been studied further. Molecular modelling of the interactions of the functional groups of AG18051 with ABAD and NAD+ has led to the targeted design of analogs with predicted improved activity. We have developed a simplified synthesis of the parent scaffold and characterized a library of AG18051 analogs possessing structural diversity. Several derivatives possess more potent ABAD inhibition than the AG18051 parent and show the translational effect to ameliorate Aβ-induced toxicity in in vitro model systems.

Synthesis and structure-activity relationship studies of the ABAD inhibitor AG18051 for Alzheimer’s disease drug development

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.