Abstract
AbstractBackgroundNeurotrophin pathways, such as those mediated by NGF and BDNF, have in numerous studies been shown to be important for neuronal cell function, communication and cell survival in brain areas vital for cognitive function. Therefore, enhancers of NGF and BDNF signaling through positive allosteric modulation of the TrkA and TrkB receptors may be a valuable new option for the treatment of cognitive decline in various disease states. The aim of this study was to identify and characterize compounds that potently stimulate neurotrophin signaling by binding to the Trk‐receptors and to investigate the effects of such a compound in various preclinical model. Moreover, the aim was also to assess its safety and tolerability in both animals and man.MethodAll binding studies were performed using a Biacore instrument. The effects of ACD856 were investigated in different preclinical in vivo behavioural models to assess its effect on cognitive function. Safety and toxicology studies were subsequently conducted in line with regulatory requirements before a microdosing study in humans was performed to evaluate the pharmacokinetics, safety and tolerability in man.ResultA binding site on the intracellular domain of TrkA was observed for the compound ACD856 using surface plasmon resonance experiments. In an in vitro kinase assay using human full‐length TrkA, ACD856 could significantly increase the apparent maximal velocity (Vmax(app)) of TrkA. ACD856 also demonstrated potent pro‐cognitive effects in vivo, with a favorable PK profile. The compound was shown to be safe and well tolerated in the preclinical toxicological studies. Micodosing results in man showed that ACD856 had a profile suitable for further clinical develoment.ConclusionThe in vitro results suggests that ACD856 binds directly to the TrkA receptor to increase the number of catalytic cycles per timepoint. This mechanism of action is a probably a likely cause for the observed in vivo effects with respect to improved cognitive performance. These data suggest that ACD856 may have a beneficial effect on cognition in patients with cognitive dysfunction and the compound is currently in clinical development for the treatment of cognitive dysfunction in Alzheimer’s disease.
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