Abstract

Neurotrophins (NT) are a class of structurally related proteins that regulate neuronal function, survival and plasticity. The family of neurotrophins includes nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), NT3 and NT4/5. A large body of genetic, pathological and mechanistic evidence suggests that loss of NGF and/or BDNF signaling contributes to the dysfunction and loss of basal forebrain cholinergic neurons and hippocampal neurons during the course of Alzheimer’s disease. Based on this body of evidence, AlzeCure initiated a drug discovery program aimed at identifying positive modulators of neurotrophin signaling as novel therapeutics for AD.
During the course of this drug discovery program, a number of novel small molecule positive modulators of NGF/TrkA- and BDNF/TrkB-signaling have been identified. In this presentation, we will describe the screening cascade and the characterization of several chemical series in recombinant cell-based assays, biochemical assays, native systems and functional assays including ERK phosphorylation in primary cortical neurons and ex vivo long-term potentiation (LTP) in rat brain slices. Characterization of lead compounds and their effects on ERK phosphorylation in rat hippocampus and in different in vivo efficacy models have led to the selection of the clinical candidate ACD855, which is currently in pre-clinical development as a symptomatic treatment with strong disease modifying potential for AD.