Rho-associated coiled-coil containing protein kinase (ROCK) inhibition represents a promising therapeutic approach for Alzheimer's disease that targets multiple disease mechanisms: neuroprotection, actin cytoskeleton modulation, dendritic spine remodeling, and cerebral blood flow enhancement. This page tracks companies developing ROCK inhibitors for AD.
- Neuroprotection: ROCK inhibition protects against Aβ-induced neuronal death
- Cytoskeleton modulation: Reduces actin stress fiber formation, improves neurite outgrowth
- Dendritic spine remodeling: Promotes synaptic plasticity and spine density
- Cerebral blood flow: Vasodilatory effects improve cerebral perfusion
- Axonal regeneration: Promotes axonal outgrowth after injury
| Isoform |
Expression |
Therapeutic Target |
| ROCK1 |
Ubiquitous |
Cytoskeleton, inflammation |
| ROCK2 |
Neurons, smooth muscle |
Synaptic plasticity, vasodilation |
| Company |
Compound |
Stage |
Mechanism |
| Eidogen/Ascend |
Fasudil |
Preclinical |
Broad ROCK inhibition |
| Kowa |
KD-1 |
Preclinical |
ROCK1/2 selective |
| Wyeth |
Wf-536 |
Discontinued |
ROCK inhibition |
| Santen |
Y-39983 |
Preclinical |
Ocular/CNS |
| Schering |
SAR407899 |
Preclinical |
Vascular effects |
| Kissei |
RKI-983 |
Preclinical |
Neuroprotection |
| Denali |
DNL921 |
Discovery |
Brain-penetrant |
| Cerevel |
CVL-231 |
Phase 1 |
CNS-selective |
¶ Preclinical and Discovery Programs
Fasudil (Eidogen/Ascend):
- First ROCK inhibitor approved in Japan (cerebral vasospasm)
- Being reformulated for CNS delivery
- Evidence in AD mouse models: improves cognition, reduces Aβ
Denali Therapeutics:
- ROCK program: DNL921
- Brain-penetrant ROCK inhibitor
- Focus on combination with other mechanisms
- Indication: Alzheimer's disease (preclinical)
Cerevel Therapeutics:
- CVL-231: CNS-selective ROCK inhibitor
- Phase 1 studies in healthy volunteers
- Potential for AD treatment
- Also: CVN424 (D1/D5 partial agonist with D3 activity)
GabMed Pharmaceuticals:
- GMP-101: ROCK2-selective inhibitor
- Stage: Discovery
- Focus: Neuroprotection
Nerviano Istituto:
- NIR-002: Pan-ROCK inhibitor
- Stage: Preclinical
- Focus: Cerebral blood flow
- AD models: ROCK inhibitors reduce Aβ toxicity in neurons
- Memory improvement: Enhanced spatial memory in Morris water maze
- Synaptic markers: Increased synaptophysin, PSD95 expression
- Blood flow: Improved cerebral blood flow in AD models
- Peripheral side effects: Hypertension, hepatotoxicity
- Narrow therapeutic window: Dose-limiting toxicity
- Isoform selectivity: Pan-ROCK vs. selective inhibition
- Brain penetration: Many first-gen inhibitors don't cross BBB
| Approach |
Target |
Stage |
Advantage |
| ROCK inhibitors |
Cytoskeleton, blood flow |
Preclinical |
Multi-target |
| Anti-amyloid |
Aβ plaques |
Approved |
Disease-modifying |
| Tau immunotherapy |
Tau tangles |
Phase 3 |
Disease-modifying |
| BACE inhibitors |
Aβ production |
Halted |
Validated target |
- Isoform-selective inhibitors: ROCK2-selective for CNS
- Brain-penetrant formulations: Improved delivery
- Combination therapy: ROCK + other mechanisms
- Prodrug approaches: Masked delivery to CNS
Related therapeutics:
Related mechanisms:
- Fasudil in AD models (2020)
- ROCK inhibition and synaptic plasticity (2021)
- Denali ROCK program (2023)