Dapansutrile (OLT1177) for Parkinson's Disease
<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">dapansutrile-parkinsons-disease</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Value</td>
</tr>
<tr>
<td class="label">Oral bioavailability</td>
<td>>70%</td>
</tr>
<tr>
<td class="label">Half-life</td>
<td>4-6 hours</td>
</tr>
<tr>
<td class="label">Cmax</td>
<td>2-4 hours</td>
</tr>
<tr>
<td class="label">Distribution</td>
<td>Primarily peripheral</td>
</tr>
<tr>
<td class="label">Protein binding</td>
<td>~60%</td>
</tr>
<tr>
<td class="label">Metabolism</td>
<td>Hepatic</td>
</tr>
<tr>
<td class="label">Excretion</td>
<td>Renal</td>
</tr>
<tr>
<td class="label">Change</td>
<td>Potential Effect</td>
</tr>
<tr>
<td class="label">Increased Prevotellaceae</td>
<td>Reduced mucin production</td>
</tr>
<tr>
<td class="label">Decreased Firmicutes/Bacteroidetes ratio</td>
<td>Altered fermentation products</td>
</tr>
<tr>
<td class="label">Increased Enterobacteriaceae</td>
<td>Pro-inflammatory endotoxins</td>
</tr>
<tr>
<td class="label">Decreased Faecalibacterium</td>
<td>Reduced anti-inflammatory SCFAs</td>
</tr>
<tr>
<td class="label">Inhibitor</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Dapansutrile</td>
<td>NLRP3 ATPase</td>
</tr>
<tr>
<td class="label">MCC950</td>
<td>NLRP3</td>
</tr>
<tr>
<td class="label">科尔vc</td>
<td>Multiple</td>
</tr>
<tr>
<td class="label">Parthenolide</td>
<td>Multiple</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Details</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase 2</td>
</tr>
<tr>
<td class="label">Design</td>
<td>Randomized, double-blind, placebo-controlled</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>52 weeks</td>
</tr>
<tr>
<td class="label">Sample size</td>
<td>~120 patients</td>
</tr>
<tr>
<td class="label">Primary endpoint</td>
<td>MDS-UPDRS Part III (Motor Examination)</td>
</tr>
<tr>
<td class="label">Secondary endpoints</td>
<td>MDS-UPDRS Parts I/II, Non-motor symptoms, Biomarkers</td>
</tr>
<tr>
<td class="label">Sponsor</td>
<td>Olatec Therapeutics</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Recruiting</td>
</tr>
<tr>
<td class="label">Drug/Approach</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Dapansutrile</td>
<td>NLRP3</td>
</tr>
<tr>
<td class="label">Minocycline</td>
<td>Microglia (broad)</td>
</tr>
<tr>
<td class="label">CoQ10</td>
<td>Mitochondria</td>
</tr>
<tr>
<td class="label">Azathioprine</td>
<td>Immunosuppression</td>
</tr>
<tr>
<td class="label">N-acetylcysteine</td>
<td>Antioxidant</td>
</tr>
<tr>
<td class="label">Infliximab</td>
<td>TNF-α</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Rationale</td>
</tr>
<tr>
<td class="label">+Levodopa</td>
<td>Complementary mechanisms</td>
</tr>
<tr>
<td class="label">+MAO-B inhibitor</td>
<td>Additive anti-inflammatory</td>
</tr>
<tr>
<td class="label">+Physical therapy</td>
<td>Multi-modal approach</td>
</tr>
<tr>
<td class="label">+GDNF agonists</td>
<td>Neuroprotective synergy</td>
</tr>
<tr>
<td class="label">Adverse Event</td>
<td>Frequency</td>
</tr>
<tr>
<td class="label">Headache</td>
<td>10-15%</td>
</tr>
<tr>
<td class="label">Nausea</td>
<td>5-10%</td>
</tr>
<tr>
<td class="label">Diarrhea</td>
<td>5-8%</td>
</tr>
<tr>
<td class="label">Upper respiratory infection</td>
<td>5-10%</td>
</tr>
<tr>
<td class="label">Fatigue</td>
<td>3-7%</td>
</tr>
</table>
Overview
Dapansutrile (formerly known as OLT1177) is a novel, selective, and potent oral small-molecule inhibitor of the NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome developed by Olatec Therapeutics[@marchetti2018]. It represents one of the most advanced NLRP3 inhibitors in clinical development and is currently being evaluated in a Phase 2 clinical trial specifically for Parkinson's Disease (NCT07157735)[@clinicaltrialsgov]. The therapeutic rationale for dapansutrile in PD stems from the critical role of neuroinflammation in disease pathogenesis, with the NLRP3 inflammasome serving as a central driver of chronic neuroinflammation and dopaminergic neuron loss[@haque2020][@chen2020].
Chemical and Pharmacological Properties
Chemistry
Dapansutrile is a beta-sulfonyl nitrile compound with favorable drug-like properties:
- Chemical name: (E)-3-(4-(methylsulfonyl)phenyl)-2-phenyl-2-propenenitrile
- Molecular formula: C18H18N4O3S
- Molecular weight: 370.43 g/mol
- Mechanism: Direct binding to the NLRP3 ATPase domain
- Selectivity: High specificity for NLRP3 over other NLR family members (NLRP1, NLRP2, NLRC4)
- Formulation: Oral tablet
- Blood-brain barrier penetration: Limited peripheral distribution; CNS effects via gut-brain axis[@marchetti2018]
Pharmacokinetics
Dapansutrile exhibits favorable pharmacokinetic properties suitable for chronic oral administration:
The relatively short half-life supports twice-daily dosing while maintaining consistent NLRP3 inhibition throughout the day.
Selectivity Profile
Dapansutrile demonstrates high selectivity for NLRP3:
- NLRP3: Ki < 100 nM (potent inhibition)
- NLRP1: >10 μM (no significant inhibition)
- NLRC4: >10 μM (no significant inhibition)
- NLRP2: >10 μM (no significant inhibition)
- Other kinases: No significant off-target effects
This selectivity profile minimizes the risk of unexpected side effects from targeting related inflammasome pathways.
Mechanism of Action
NLRP3 Inflammasome Biology
The NLRP3 inflammasome is a multimeric protein complex that plays a critical role in innate immune responses[@schroder2010]. It functions as a molecular platform for activating caspase-1, which then processes the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) into their mature, secreted forms[@broz2010].
Inflammasome activation occurs in two signals:
Priming signal (Signal 1): NF-κB-mediated transcription of NLRP3, pro-IL-1β, and pro-IL-18
Activation signal (Signal 2): Various danger signals trigger NLRP3 assembly into the inflammasome complexDapansutrile's Molecular Mechanism
Dapansutrile inhibits NLRP3 inflammasome activation through direct binding to the NLRP3 ATPase domain[@faustin2017]:
Direct binding: Dapansutrile binds to the NACHT domain of NLRP3, blocking ATP hydrolysis
Oligomerization prevention: By inhibiting ATP binding, dapansutrile prevents NLRP3 self-oligomerization
ASC speck blockade: Prevents NLRP3 from recruiting the adaptor protein ASC
Caspase-1 inhibition: Blocks the activation of pro-caspase-1 to active caspase-1
Cytokine blockade: Prevents processing and secretion of IL-1β and IL-18Mermaid diagram (expand to render)
Downstream Effects
By reducing IL-1β and IL-18 production, dapansutrile attenuates multiple downstream inflammatory pathways[@kelley2018]:
- IL-1β effects: Reduces activation of IL-1R on microglia and neurons, decreasing NF-κB activation and pro-inflammatory gene expression
- IL-18 effects: Attenuates interferon-γ production and Th1 responses
- Microglial deactivation: Shifts microglia from M1 (pro-inflammatory) to M2 (neuroprotective) phenotype
- Reduced cytokine cascade: Decreases production of other inflammatory mediators (TNF-α, IL-6, COX-2)
The Gut-Brain Axis Connection
NLRP3 and the Gut Microbiome in Parkinson's Disease
The gut-brain axis has emerged as a critical factor in PD pathogenesis, with the NLRP3 inflammasome playing a central role in this bidirectional communication[@sampson2016].
Mechanisms of gut-brain inflammation in PD:
Gut permeability: NLRP3 activation in intestinal epithelium contributes to increased intestinal permeability ("leaky gut")[@agosta2014]
Microbiome alterations: PD patients exhibit distinct gut microbiota profiles with increased pro-inflammatory species
Vagal signaling: The vagus nerve transmits inflammatory signals from the gut to the brain[@bonaz2018]
Systemic inflammation: Circulating inflammatory cytokines cross or influence the blood-brain barrierGut Permeability and PD
Patients with Parkinson's disease commonly exhibit increased intestinal permeability[@devos2013]:
- Tight junction disruption: NLRP3 activation in gut epithelial cells disrupts tight junction proteins
- Endotoxin translocation: Lipopolysaccharide (LPS) from gram-negative bacteria enters systemic circulation
- Immune activation: Systemic endotoxin exposure primes peripheral immune cells
- Neuroinflammation propagation: Activated immune cells traffic to the CNS
Dapansutrile's oral administration allows for potential effects on gut NLRP3, which may help restore gut barrier integrity and reduce systemic inflammation.
Microbiome Modulation
The gut microbiota in PD patients shows characteristic alterations[@claesson2012]:
Dapansutrile may indirectly modulate microbiome-related inflammation by reducing intestinal NLRP3 activation.
Preclinical Evidence
MPTP Model Studies
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model is a well-established preclinical model of PD. Studies with dapansutrile have demonstrated significant neuroprotective effects[@liang2020]:
Key findings:
- Reduced dopaminergic neuron loss in substantia nigra pars compacta (SNc)
- Decreased microglial activation (Iba-1 immunoreactivity)
- Improved behavioral outcomes (rotarod, cylinder test)
- Reduced striatal dopamine depletion
- Decreased IL-1β levels in the SNc
Dosing regimens tested:
- Pre-treatment: 50 mg/kg daily for 7 days before MPTP
- Post-treatment: 50 mg/kg daily starting 24 hours after MPTP
- Both regimens showed comparable efficacy
6-OHDA Model
The 6-hydroxydopamine (6-OHDA) model provides complementary evidence for dapansutrile's neuroprotective effects[@yan2022]:
Key findings:
- Reduced lesion size in the striatum
- Preserved tyrosine hydroxylase (TH) immunoreactivity
- Decreased microglial infiltration
- Attenuated caspase-1 activation
- Improved amphetamine-induced rotation
Mechanism Studies
Preclinical studies have elucidated the neuroprotective mechanisms:
Microglial deactivation: Dapansutrile shifts microglia from M1 to M2 phenotype
Reduced cytokine production: Lower IL-1β and IL-18 in SNc
Decreased NLRP3 expression: Reduced NLRP3 and ASC in activated microglia
Preserved dopamine neurons: Maintained TH-positive neuron counts
Improved function: Better performance on behavioral testsComparison with Other NLRP3 Inhibitors
Clinical Trial: NCT07157735
Trial Design
The Phase 2 clinical trial represents a critical milestone for dapansutrile in PD:
Patient Population
Inclusion criteria:
- Diagnosis of Parkinson's disease (UK PD Society Brain Bank criteria)
- Hoehn & Yahr stage 2-3
- Age 40-80 years
- On stable dopaminergic therapy for ≥4 weeks
Exclusion criteria:
- Atypical parkinsonism
- Significant cognitive impairment
- Active inflammatory disease
- Prior NLRP3-targeted therapy
Rationale
The clinical development is supported by strong scientific rationale[@zhang2018][@blumdegen1995][@meng2019]:
Genetic evidence: NLRP3 polymorphisms associated with PD risk[@zhang2018]
Biomarker evidence: Elevated IL-1β in PD CSF and substantia nigra
Pathology evidence: NLRP3 activation in PD brain tissue
Preclinical evidence: Robust protection in animal models
Safety profile: Well-tolerated in previous clinical trialsBiomarker Strategy
The trial incorporates biomarker assessments to validate target engagement:
- Peripheral biomarkers: IL-1β, IL-18 in plasma and CSF
- Inflammatory markers: CRP, TNF-α, IL-6
- Neurodegeneration markers: Neurofilament light chain (NfL)
- Microglial imaging: TSPO PET to assess neuroinflammation
Comparison to Other Anti-inflammatory Approaches
Multiple anti-inflammatory strategies have been explored for PD:
Why NLRP3 specifically:
- Central hub for neuroinflammation
- Required for IL-1β processing
- Activated in PD brain
- Selectively targeted by dapansutrile
Therapeutic Implications
Potential Benefits
Disease modification: Targeting upstream inflammation may slow disease progression
Symptomatic benefit: Reduced neuroinflammation may improve motor and non-motor symptoms
Peripheral effects: Gut-brain axis modulation may improve GI symptoms
Combination potential: Compatible with dopaminergic therapiesChallenges and Limitations
BBB penetration: Limited CNS exposure may reduce direct brain effects
Timing: May be most effective in early disease stages
Chronic treatment: Long-term safety requires extended monitoring
Biomarker validation: Surrogate endpoints need validationPatient Selection
Optimal candidates for dapansutrile therapy:
- Early to mid-stage PD (Hoehn & Yahr 2-3)
- Evidence of elevated inflammation (elevated cytokines)
- Intact gut barrier function
- No significant cognitive impairment
- On stable PD medications
Combination Strategies
Dapansutrile may synergize with other PD therapies:
Safety and Tolerability
Clinical Safety Data
Dapansutrile has been evaluated in multiple clinical trials:
- Completed trials: Phase 1 in healthy volunteers, Phase 2 in osteoarthritis, Phase 2 in gout
- Total subjects exposed: >500 patients
- Doses tested: Up to 1200 mg/day
Adverse Events
Most common adverse events (≥5%):
Drug Interactions
- Limited CYP-mediated interactions
- No significant food effects
- Compatible with standard PD medications
Related Pages
- [NLRP3 Inflammasome in Neurodegeneration](/mechanisms/nlrp3-inflammasome)
- [NLRP3 Inhibitors for Neurodegeneration](/therapeutics/nlrp3-inhibitors-neurodegeneration)
- [NLRP3 Protein](/proteins/nlrp3)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Microglia in Neuroinflammation](/cell-types/microglia-neuroinflammation)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
- [Neuroinflammation in Parkinson's Disease](/mechanisms/neuroinflammation-parkinsons-disease)
- [Gut-Brain Axis in Neurodegeneration](/mechanisms/gut-brain-axis-neurodegeneration)
- [Dopaminergic Neurons](/cell-types/dopaminergic-neurons)
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Neuroinflammation Mechanisms](/mechanisms/neuroinflammation)
- [Inflammasome Biology](/mechanisms/inflammasome-biology)
External Links
- [ClinicalTrials.gov - NCT07157735](https://clinicaltrials.gov/study/NCT07157735)
- [PubMed - NLRP3 and Parkinson's](https://pubmed.ncbi.nlm.nih.gov/?term=nlrp3+parkinson)
- [Olatec Therapeutics](https://www.olatec.com/)
- [Michael J. Fox Foundation](https://www.michaeljfox.org/)
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