Phosphodiesterase 5 (PDE5) is an enzyme that catalyzes the degradation of cyclic guanosine monophosphate in a variety of tissues including the brain and has been indicated as a promising target for the treatment of Alzheimer’s Disease (AD). In this study, we designed and synthesized new molecules based on the indole ring and tested PDE5 activity. Previous studies have showed that quinoline-based molecules were effective at inhibiting PDE5 and rescuing learning and memory in several AD animal models. Thus, we hypothesized that the replacement of the quinoline ring with the indole ring could provide a new class of PDE5 inhibitors. The new derivatives were chosen based on the synthetic amenability of the indole ring compared to the quinoline ring, while retaining their aromatic functional group. Additionally, the presence of the indole ring in numerous biological molecules and pharmaceuticals encouraged us to explore the biological activity of this chemical structure.<br/>We designed two different scaffolds (A and B) based on the position of the amino group. The synthesis of scaffold A only was successfully completed and provided us with a small library of new derivatives (1A-4A). We tested these compounds for PDE5 activity in a primary enzymatic assay at a concentration of 10 µM. An in-house enzymatic assay was developed based on LC/MS analysis. While compounds 1A and 2A showed 10% and 23% inhibition of PDE5, respectively, compounds 3A and 4A showed 72% and 77% inhibition, respectively, suggesting that they possess biological activity towards the enzyme in the low micromolar range.<br/>Our future aims are to measure the potency and selectivity of these molecules against the full panel of PDE enzymes and evaluate their ability to increase synaptic plasticity using electrophysiological experiments. Furthermore, we will expand the library of indole-based molecules to assess the structure-activity relationship and find compounds with lower potency.

Design and synthesis of indole derivatives as phosphodiesterase 5 inhibitors for the treatment of Alzheimer’s disease

ACS Spring 2022

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