P1-307: Inhibition of protein misfolding by optimization of small molecules targeted to both beta-amyloid and tau peptides

Protein misfolding followed by aberrant protein oligomerization and subsequent aggregation of both beta-amyloid and tau is often implicated in the development of AD. The clinical presentation of AD is heterogeneous (e.g. extrapyramidal symptoms in some people with AD and dementia symptoms in some people with PD). The clinical overlap amongst neurodegenerative disorders implies that AD is more of a syndrome than a disease and that the suppression of other aberrantly misfolded protein may afford additional therapeutic benefits. Accordingly, we are seeking to design and develop brain-penetrable small molecule new chemical entities targeting protein misfolding in general and both beta-amyloid and tau specifically. Based upon extensive in silico modelling a family of novel compounds has been identified. A representative compound is TRV 101. Efficacy of TRV 101 in prevention of oligomerization was measured in vitro using biotin- beta-amyloid and biotin- tau assays. TRV 101 binding to beta-amyloid and tau 4NR2 was measured by Surface Plasmon Resonance (SPR). In vitro ADMET data along with mouse pharmacokinetics/ bioavailability (plasma and brain) was collected. TRV 101 demonstrated prevention of oligomerization activity against both beta-amyloid and tau. TRV 101 showed selective binding of the target protein by surface plasmon resonance (SPR). TRV 101 has optimum drug like properties, demonstrating favourable in vitro ADMET, high brain penetrance and oral bioavailability, and is benign in a 44-receptor panel test. We have designed and developed a new class of compounds capable of inhibiting oligomerization of both beta-amyloid and tau proteins. Our small molecules have appropriate pharmacokinetic profiles and are able to reach the target tissue. Our compounds are currently being tested in several animal models of both beta-amyloid and tau pathologies.