[P4–031]: ALZHEIMER'S DISEASE AS A DISORDER OF TRYPTOPHAN METABOLISM

Novel druggable targets are needed in the search for new chemical entities as putative therapeutics for Alzheimer's disease (AD) and related protein misfolding disorders. Increasingly, the role of the immune system in the pathogenesis of AD is being appreciated. Indoleamine-2,3-dioxygenase (IDO) is an enzyme involved in the metabolism of tryptophan, and which influences the balance of pro-inflammatory and anti-inflammatory cytokines with the central nervous system. This project targets IDO-1 as a possible target for the design of desease modifying drugs for AD. Specifically, it targets synthetic analogues of tryptophan as potential competitive inhibitors of IDO. Commencing with the known crystal structure of IDO-1, extensive molecular modelling calculations, using GROMACS and MOE software, were performed to provide three-dimensional representations of the interactions of tryptophan and some of its indoleamine metabolites with the enzyme's active site. Specifically, empirical force field and molecular mechanics/quantum mechanics hybrid calculations were employed. Based upon these calculations, a family of novel stilbene-derivatized indoles was devised. They were prepared using a variety of synthetic strategies but the Negishi-Stille and Knoevenagel-Doebner reactions offered the greatest synthetic flexibility and utility. Using these synthetic strategies, a focussed library of 72 compounds was prepared. All compounds were evaluated for inhibition of IDO-1 in human recombinant enzyme, transfected HEK293 cells and interferon-γ stimulated human microglia. Finally, a representative compound was evaluated in the APP/PS1 transgenic mouse model using both behavioural and histopathological markers. Multiple 3-substituted stilbene derivatives of indole demonstrated low micromolar activity as competitive inhibitors of the IDO-1 enzyme. No nanomolar inhibitors were obtained from this analogue series. A representative bi-aromatic analogue from this class, at doses of 25 mg/kg/od from ages 2–6 months of age, demonstrated improved behavioural measures in both the Morris Water Maze and Radial Arm Water Maze tests. This compound class is worthy of continued development as a druggable molecular platform. The tryptophan metabolic pathway is a novel druggable target for the design and synthesis of new chemical entities, targetting the IDO-1 enzyme, as possible disease modifying agents for AD.

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