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Etazolate (EHT-0202) is a fascinating triple-mechanism molecule: a 1970s pyrazolopyridine anxiolytic that ExonHit repurposed for Alzheimer's disease. In one compound it combines PDE4 inhibition, positive allosteric modulation of GABA-A receptors, and stimulation of alpha-secretase, which raises the neurotrophic, neuroprotective fragment sAPPalpha and steers amyloid precursor protein away from toxic amyloid. It is one of the few compounds in this class to have actually completed a placebo-controlled Phase 2 trial in Alzheimer's patients.
- Unusual triple mechanism (PDE4 + GABA-A PAM + alpha-secretase) in a single molecule
- Raises neurotrophic, neuroprotective sAPPalpha
- Spatial-memory gains in aged rodents
- Real human safety data from a completed Phase 2 Alzheimer's trial
- Dose-dependent CNS adverse events and early trial withdrawals
- Sedation and CNS-depressant potential from GABA-A/barbiturate-site activity
- PDE4-class GI effects
- It is one of the very few PDE4-adjacent compounds to complete an actual placebo-controlled Phase 2 trial in Alzheimer's patients.
- Its neuroprotective sAPPalpha boost is blocked by GABA-A antagonists, meaning its lead mechanism is GABA-A-driven rather than PDE4-driven.
- It began life in the 1970s as an anxiolytic before being reinvented decades later as an Alzheimer's candidate.
Mechanism
Three actions in one molecule: (1) PDE4 inhibition raises ; (2) positive modulation of -A at the barbiturate/etazolate site (its original anxiolytic action); and (3) alpha-secretase stimulation that raises neurotrophic sAPPalpha. Marcade 2008 showed the sAPPalpha induction and neuroprotection are blocked by GABA-A antagonists, so the lead Alzheimer's mechanism is GABA-A-linked, with PDE4/cAMP secondary. Exact PDE4 IC50 and -antagonism figures come from secondary sources and are flagged as uncertain.
receptor fingerprint
-A receptor (barbiturate/etazolate site)Positive allosteric modulator
Alpha-secretaseStimulates
PDE4Inhibits
A1/A2 receptorsAntagonizes (historical)
Evidencehow good the literature is
Human RCT evidence (Phase IIa in Alzheimer's) established safety, not efficacy: a 3-month trial added to acetylcholinesterase inhibitors found it safe and tolerable with dose-dependent CNS adverse events and early withdrawals, and no significant efficacy beyond an ADCS-ADL signal (trial NCT00880412). Preclinical work is stronger: in vitro and rodent studies show sAPPalpha stimulation, GABA-A-dependent amyloid-beta neuroprotection, and spatial-memory gains in aged rats.
Dosingtypical ranges, not medical advice
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Safetyrisks and cautions, not medical advice
Described as safe and generally well tolerated in the RCT, but with dose-dependent CNS adverse events and early withdrawals. Expect the PDE4-class GI cluster plus sedation and CNS-depressant potential from the GABA-A / barbiturate-site activity, which can be additive with other CNS depressants such as alcohol and benzodiazepines. It is investigational and discontinued, with efficacy never demonstrated.
History
First synthesized in the 1970s as SQ-20009, an experimental anxiolytic, etazolate was later revived by ExonHit Therapeutics as EHT-0202 on the strength of its unusual triple mechanism. It advanced to a Phase IIa Alzheimer's trial (completed 2009) but the underpowered, essentially null result ended its development.
Reputation
Among researchers it is prized as a teaching example of multi-target Alzheimer's pharmacology, uniting cAMP, GABA-A and amyloid-processing biology. Its reputation is that of a scientifically elegant near-miss rather than a viable therapy, given the halted program.
Subjective profileweighing the evidence above
A genuinely interesting triple-mechanism compound with real human safety data from an Alzheimer's Phase 2 trial. Honestly, though, that trial was underpowered and essentially null on efficacy, and development was halted, so its clinical promise remains unproven.
Resources
This entry is here for reference.
Research
- 2008first citedEtazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor pr…
- 2014most recentEtazolate abrogates the lipopolysaccharide (LPS)-induced downregulation of the cAMP/pCREB/BDNF…
- 1.Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing.
- 2.EHT0202 in Alzheimer's disease: a 3-month, randomized, placebo-controlled, double-blind study.
- 3.Etazolate improves performance in a foraging and homing task in aged rats.
- 4.Etazolate abrogates the lipopolysaccharide (LPS)-induced downregulation of the cAMP/pCREB/BDNF signaling, neuroinflammatory response and depressive-like behavior in mice.
4 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Did etazolate work for Alzheimer's?
No. Its Phase IIa trial established safety but was underpowered and essentially null on efficacy, and development was stopped.
What makes its mechanism unusual?
It acts on three fronts at once: PDE4 inhibition, GABA-A positive allosteric modulation, and alpha-secretase stimulation that raises protective sAPPalpha.
Can it be combined with sedatives?
Caution is warranted: its GABA-A/barbiturate-site activity can be additive with alcohol, benzodiazepines and other CNS depressants.
Limitations of the evidence
- Investigational and discontinued; efficacy never demonstrated
Adverse effects
- Dose-dependent CNS adverse events and early trial withdrawals
- Sedation and CNS-depressant potential from GABA-A/barbiturate-site activity
- PDE4-class GI effects