title: Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease.
abstract: In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrP(Sc)) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood-brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases.
authors.affiliation: Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 23, 81377, Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wagner
authors.forename: Sergey
authors.initials: S
authors.lastname: Ryazanov
authors.forename: Andrei
authors.initials: A
authors.lastname: Leonov
authors.forename: Johannes
authors.initials: J
authors.lastname: Levin
authors.forename: Song
authors.initials: S
authors.lastname: Shi
authors.forename: Felix
authors.initials: F
authors.lastname: Schmidt
authors.forename: Catharina
authors.initials: C
authors.lastname: Prix
authors.forename: Francisco
authors.initials: F
authors.lastname: Pan-Montojo
authors.forename: Uwe
authors.initials: U
authors.lastname: Bertsch
authors.forename: Gerda
authors.initials: G
authors.lastname: Mitteregger-Kretzschmar
authors.forename: Markus
authors.initials: M
authors.lastname: Geissen
authors.forename: Martin
authors.initials: M
authors.lastname: Eiden
authors.forename: Fabienne
authors.initials: F
authors.lastname: Leidel
authors.forename: Thomas
authors.initials: T
authors.lastname: Hirschberger
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Deeg
authors.forename: Julian J
authors.initials: JJ
authors.lastname: Krauth
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zinth
authors.forename: Paul
authors.initials: P
authors.lastname: Tavan
authors.forename: Jens
authors.initials: J
authors.lastname: Pilger
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.forename: Tobias
authors.initials: T
authors.lastname: Frank
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Ulrike
authors.initials: U
authors.lastname: Teichmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Samwer
authors.forename: Kai
authors.initials: K
authors.lastname: Bötzel
authors.forename: Martin
authors.initials: M
authors.lastname: Groschup
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D017096:Prion Diseases / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D011328:Prions / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000819:agonists*; D011743:Pyrimidines / Q000819:agonists*; D012402:Rotenone / Q000494:pharmacology; D051844:alpha-Synuclein / Q000494:pharmacology
chemical_list: C493309:N(4)-benzyl-N(6),N(6)-dimethyl-1-1(tert-butyl)-1H-pyrazolo(3,4-d)pyrimidine-6,4-diamine; D011328:Prions; D011720:Pyrazoles; D011743:Pyrimidines; D051844:alpha-Synuclein; D012402:Rotenone