Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease

• DOI: 10.1007/s00401-013-1114-9
• Publication Date: 2013-04-18T16:22:12Z
• Authors: Jens Wagner; Sergey Ryazanov; Andrei Leonov; Johannes Levin; Song Shi; Felix Schmidt; Catharina Prix; Francisco Pan-Mon...; Uwe Bertsch; Gerda Mitteregger...; Markus Geissen; Martin Eiden; Fabienne Leidel; Thomas Hirschberger; Andreas A. Deeg; Julian J. Krauth; Wolfgang Zinth; Paul Tavan; Jens Pilger; Markus Zweckstetter; Tobias Frank; Mathias Bähr; Jochen H. Weishaupt; Manfred Uhr; Henning Urlaub; Ulrike Teichmann; Matthias Samwer; Kai Bötzel; Martin Groschup; Hans Kretzschmar; Christian Griesinger; Armin Giese
• Keywords: Oligomer; Synucleinopathies; Lewy body

In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates presumed to be the key neurotoxic agent. Here we describe novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. vitro, blocked formation pathological protein (PrP(Sc)) α-synuclein (α-syn), which is deposited in PD other synucleinopathies dementia Lewy bodies (DLB) multiple system atrophy (MSA). Notably, strongly inhibited all strains tested including BSE-derived human prions. Anle138b showed structure-dependent binding oligomers vitro vivo both for α-synuclein. Both mouse models three different models, accumulation, neuronal degeneration, progression vivo. had no detectable toxicity at therapeutic doses excellent oral bioavailability blood-brain-barrier penetration. Our findings indicate that modulators provide new approach disease-modifying therapy these only symptomatic treatment available so far. Moreover, our suggest share structural features, although main component disease-specific, indicating compounds modulate by targeting epitopes can have broad spectrum activity diseases.