Neurodegeneration drug development is brutal. The brain hides behind a fortress blood-brain barrier. Neurons don't divide, so you can't target proliferation. Diseases progress over decades, meaning trials need biomarkers that move faster than clinical decline.

But some targets do yield to small molecules. The trick is distinguishing between what's biologically important and what's pharmacologically accessible.

What's Actually Working

Mitochondrial Permeability Transition Pore (mPTP)

NRG5051—a selective mPTP inhibitor from NRG Therapeutics—entered Phase 1 trials in January 2026 for ALS and Parkinson's. This target has real advantages: it's an ion channel (druggable by small molecules), it sits upstream of multiple pathologies, and there's a validated biomarker (NfL) for rapid readout. Preclinical data show reduced neuroinflammation and preserved motor neurons.

PDE4/PDE10 Inhibition

Ibudilast (MN-166) wrapped Phase 2 in ALS. It's an oral small molecule with decades of safety data from Japanese asthma markets. The mechanism—reducing inflammatory cytokines via phosphodiesterase inhibition—is well-understood and tractable.

AMPK Activation

Metformin, an FDA-approved AMPK activator, is in Phase 2 for C9orf72-associated ALS/FTD. Repurposing an approved drug removes much of the safety risk that kills early-phase programs.

What Keeps Failing

Direct Protein Aggregation Targeting

Small molecules that disaggregate amyloid or tau have failed repeatedly. Binding to aggregated proteins is hard. Even successful binding doesn't clearly improve cellular function. Biologics work better here because they tag aggregates for clearance—small molecules lack this mechanism.

Direct Axon Regeneration

PTEN inhibition, RhoA blockers, and LINGO-1 antibodies all regrow axons in rodents. None have translated to humans. The problem: mammalian CNS neurons lose regenerative capacity through multiple redundant mechanisms. A single small molecule hitting one pathway cannot overcome this.

Growth Factor Delivery

BDNF and GDNF are neuroprotective but they're proteins—they don't cross the BBB, require injection, and cause side effects. Small molecule TrkB agonists try to bypass this, but bioavailability remains problematic.

The Druggable Sweet Spot

The targets that are succeeding share features:

1. Enzymatic or channel activity—can be modulated by small molecules with reasonable PK
2. Upstream position—affects multiple downstream pathology nodes
3. Validated biomarkers—allows rapid Phase 1/2 decision-making
4. Established biology—not novel targets with unclear mechanism

Testable Predictions

1. By 2028, mPTP inhibitors will show NfL reduction in Phase 2 neurodegeneration trials
2. No small molecule targeting direct axon regeneration will reach Phase 3 before 2030
3. The next approved ALS drug will be a repurposed small molecule, not a novel biologic

The Bottom Line

We are not going to cure ALS or Alzheimer's with small molecules alone. But we might slow them. The targets yielding to medicinal chemistry—mitochondrial dynamics, protein homeostasis, inflammation—are where small molecules can make a difference. The dream of drugs that regrow neurons or dissolve plaques remains just that: a dream. The reality is incremental preservation of function through tractable biology.

Research synthesis via Aubrai