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Name: Anle138b
Chemical Name: 3-(1,3-Benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline), alpha-synuclein, Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1/2)
Company: MODAG GmbH


Anle138b is an oral, brain-penetrant, general inhibitor of protein aggregation. It was identified in a high-throughput screen for small-molecule inhibitors of α-synuclein and prion protein oligomerization. The compound is being developed for treatment of the rapidly progressing synucleinopathy multiple-system atrophy (MSA) and for Parkinson's disease (PD). It could potentially be applied to other synucleinopathies, such as dementia with Lewy bodies (DLB). 

This diphenyl pyrazole compound has been shown to suppress oligomer formation in vitro and in vivo. It inhibited pathogenic protein accumulation and neurodegeneration, and improved survival in mouse models of α-synuclein and prion disease (Apr 2011 conference newsWagner et al., 2013).

In α-synuclein transgenic mouse models of PD, anle138b administration reduced protein deposition in brain and improved dopamine neuron function and movement, even when treatment began after symptoms developed (Wegrzynowicz et al., 2019; Mar 2015 conference newsLevin et al., 2014).

In a mouse model of MSA created by overexpressing human α-synuclein in oligodendrocytes, anle138b reduced α-synuclein oligomers, preserved dopaminergic neurons, and improved walking compared with nontreated controls (Heras-Garvin et al., 2019). In a model mimicking more severe MSA, anle138b slightly improved motor skills, but did not significantly change neurodegeneration or α-synuclein accumulation in glia in mice expressing α-synuclein and exposed to a mitochondrial toxin (Fellner et al., 2016).

Anle138b was also effective in mouse models of tau pathology, where treatment of young mice decreased neuron loss, increased survival, and improved cognition (Aug 2014 conference newsWagner et al., 2015). Even in older tau mice with established pathology, the compound was able to lessen tau deposition and reverse metabolic decline (Brendel et al., 2019). It inhibited tau aggregation in cell culture models, as well (Dominguez-Meijide et al., 2020).

In the APP/PS1Δ9 mouse model of Aβ pathology, anle138b restored hippocampal synaptic plasticity and memory (Martinez-Hernandez et al., 2018). A study comparing anle138b to the investigational α-synuclein immunotherapy Affitope PD03 reported that both improved PD-related outcomes such as α-syn oligomer levels, microglial activation, neurodegeneration in the substantia nigra, and gait (Lemos et al., 2020).

A PET tracer based on anle138b is in development (Kuebler et al., 2020).


In December 2019, MODAG began a Phase 1, first-in-human study of the safety, tolerability, and blood levels of orally administered anle138b in healthy adults. Held in Nottingham, U.K., the trial enrolled 68 volunteers, who received single ascending doses of 50 mg and higher, or multiple ascending doses for seven days, or matching placebo. Primary outcomes were adverse events, changes in clinical lab measures, electrocardiogram, vital signs, and physical exam. Secondary outcomes were blood concentrations of drug. An optional third study arm measured the effect of food on pharmacokinetics. The trial finished in August 2020. According to a company press release, doses up to 300 mg daily produced no side effects. The drug's half-life was 12 hours, and plasma levels significantly exceeded those required for efficacy in animal models. Uptake was not affected by food. 

In December 2020, the company began a Phase 1b study in 48 people with Parkinson’s disease, also in Nottingham. The trial will assess safety, tolerability, and pharmacokinetics of 150 mg and higher daily doses for seven days. Other endpoints include CSF drug levels and changes in motor function. The U.K. study is supported by the Michael J. Fox Foundation, and expected to conclude in June 2022.

For details on anle138b trials, see

Last Updated: 22 Jul 2022


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News Citations

  1. Barcelona: Parkinson’s Treatments on the Horizon
  2. Antibody Against α-Synuclein Looks Safe In Phase 1
  3. Therapies Take Aim at Tau

Research Models Citations

  1. APPswe/PSEN1dE9 (line 85)

Paper Citations

  1. . Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol. 2013 Jun;125(6):795-813. PubMed.
  2. . Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model. Acta Neuropathol. 2019 Oct;138(4):575-595. Epub 2019 May 31 PubMed.
  3. . The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol. 2014 Mar 11; PubMed.
  4. . Anle138b modulates α-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy. Mov Disord. 2019 Feb;34(2):255-263. Epub 2018 Nov 19 PubMed.
  5. . Anle138b Partly Ameliorates Motor Deficits Despite Failure of Neuroprotection in a Model of Advanced Multiple System Atrophy. Front Neurosci. 2016;10:99. Epub 2016 Mar 10 PubMed.
  6. . Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies. Acta Neuropathol. 2015 Nov;130(5):619-31. Epub 2015 Oct 6 PubMed.
  7. . Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau. Alzheimers Res Ther. 2019 Aug 1;11(1):67. PubMed.
  8. . Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization. Sci Rep. 2020 Jul 30;10(1):12827. PubMed.
  9. . The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology. EMBO Mol Med. 2018 Jan;10(1):32-47. PubMed.
  10. . Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance. Transl Neurodegener. 2020 Sep 24;9(1):38. PubMed.

External Citations

  1. company press release
  3. Kuebler et al., 2020

Further Reading


  1. . Quantitative Real-Time Quaking-Induced Conversion Allows Monitoring of Disease-Modifying Therapy in the Urine of Prion-Infected Mice. J Neuropathol Exp Neurol. 2015 Sep;74(9):924-33. PubMed.
  2. . Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates. Biochim Biophys Acta. 2015 Sep;1850(9):1884-90. Epub 2015 May 29 PubMed.
  3. . Resolving the Atomistic Modes of Anle138b Inhibitory Action on Peptide Oligomer Formation. ACS Chem Neurosci. 2017 Dec 20;8(12):2791-2808. Epub 2017 Sep 28 PubMed.
  4. . Photophysics of diphenyl-pyrazole compounds in solutions and α-synuclein aggregates. Biochim Biophys Acta. 2018 Apr;1862(4):800-807. Epub 2017 Dec 19 PubMed.
  5. . Anle138b prevents PrP plaque accumulation in Tg(PrP-A116V) mice but does not mitigate clinical disease. J Gen Virol. 2019 Jun;100(6):1027-1037. Epub 2019 May 2 PubMed.
  6. . Emergence of prions selectively resistant to combination drug therapy. PLoS Pathog. 2020 May;16(5):e1008581. Epub 2020 May 18 PubMed. Correction.
  7. . Novel Furan-2-yl-1H-pyrazoles Possess Inhibitory Activity against α-Synuclein Aggregation. ACS Chem Neurosci. 2020 Aug 5;11(15):2303-2315. Epub 2020 Jul 8 PubMed.
  8. . Emergence of prions selectively resistant to combination drug therapy. PLoS Pathog. 2020 May;16(5):e1008581. Epub 2020 May 18 PubMed. Correction.
  9. . Novel Furan-2-yl-1H-pyrazoles Possess Inhibitory Activity against α-Synuclein Aggregation. ACS Chem Neurosci. 2020 Aug 5;11(15):2303-2315. Epub 2020 Jul 8 PubMed.