In the context of developing therapies for dementias and cognitive decline, potent dual acting molecules targeting the GPCR 5HT6 and the enzyme HDAC6 with favorable BBB penetration profile were designed and synthesised.

Abstract

Alzheimer's Disease (AD) impacts significantly the quality of life of people aged over 65 years old, while millions more suffer from other types of dementia, yet no effective drugs exist. The few approved drugs in this area address mostly the associated symptoms, while several selective agents acting on promising targets have failed in clinical trials. The complexity of neurodegenerative diseases has prompted multitargeting ligands as the new paradigm, where more than one biological mechanism may be perturbed synergistically. In this context, we explored the design and synthesis of dual 5-ΗΤ₆ antagonists / HDAC6 inhibitors since these actions have been individually demonstrated to elicit cognitive-enhancing effects. Prototypes with this dual action on a GPCR and an enzyme were designed and synthesized by tethering an aryl-hydroxamic acid unit, an established pharmacophore for HDAC6 inhibition, to the piperazine of intepirdine, a potent 5-ΗΤ₆ antagonist. A new gram-scale synthesis of intepirdine was developed followed by attaching different types of arylhydroxamic acids. Derivative RG-283AG emerged to possess sub-micromolar potency toward HDAC6 inhibition (IC₅₀ 0.54 μμ), nanomolar affinity (K_i 0.7 nM) for 5-HT₆ receptor and favorable BBB penetration capacity, thus constituting the first example of a dual-acting 5-ΗΤ₆ / HDAC6 ligand with potential cognitive-enhancing properties.