P2-130: Phenylthiazolyl-hydrazides: A lead for tau aggregation inhibitors and tau imaging?

Abstract

The aggregation of tau protein into paired helical filaments is a key pathological feature of Alzheimer's disease. Several screening campaigns reported the “usual suspects” but few drug-like lead structures. Therefore, the HTS data on tau aggregation inhibition by small molecules created and reported by E. Mandelkow et al. were employed for an in silico approach. A ligand-based approach to tau protein aggregation into paired helical filaments resulted in successful scaffold hopping and the identification of phenythiazolyhydrazides (PTHs) as potent lead structure. Here we report the comparison of PTHs to selected curcumin derivatives and approved tetracyclines for their tau antiaggregatory properties and their affinity to fibrillar beta-amyloid in several assays and cellular models. The most potent fluorescent compounds were evaluated for beta-amyloid/tau PHF selectivity by fluorescence microscopy of human AD probes. Lead Optimization of PTHs. Several diverse PTH analogues were obtained by variation of the substituents R1-R4 to explore a preliminary SAR. Fluorescent substituents were incorporated without significantly compromising in vitro activity. Tau-biased ligands with enhanced affinity to tau paired helical filaments over beta-amyloid were identified by a panel of protein aggregation assays and fluorescence microscopy of human AD preparations. Phenylthiazolylhydrazides are potent inhibitors of tau-aggregation. The fluorescence microscopy of human AD preparation suggests a binding to growth-relevant sites of tau aggregates.