Benzoylpyrrolidine ampakine

Plain-language summaryIntrigue 48 / 100

CX-516 (ampalex) is the first benzoylpyrrolidine ampakine, developed at Cortex Pharmaceuticals. Phase 2 trials in schizophrenia and Alzheimer were inconclusive. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundEstablished workhorse

33/100

First-generation AMPA PAM prototype with poor PK and mixed Phase 2 results, now largely superseded by later ampakines

Look, CX-516 matters historically. It was the compound that proved you could take an AMPA receptor positive allosteric modulator into humans and not immediately break things. Gary Lynch’s group at UC Irvine built a real pharmacological hypothesis around AMPA potentiation driving BDNF release and synaptic consolidation, and Cortex Pharmaceuticals ran it all the way through Phase 2 trials. That took real effort and the mechanism story is still interesting. We dont score for effort, though.

Here’s the thing about CX-516’s pharmacokinetics: they’re bad. Half-life around one to two hours, low oral bioavailability, and doses in the clinical trials running from 200 to 1200 mg administered three to four times daily just to maintain any exposure. That dose burden alone tells you this compound wasnt built for translation. The trials in mild cognitive impairment, schizophrenia cognitive symptoms, and fragile X syndrome all produced results that were mixed at best and insufficient to justify Phase 3 advancement. When three different indications each fail to generate a clear signal, the compound’s translational story becomes very hard to defend.

The AMPA PAM mechanism itself still draws serious attention. Positive allosteric modulation of AMPA receptors can enhance synaptic throughput without the direct receptor overstimulation risks of AMPA agonism, and the downstream effects on BDNF and long-term potentiation are mechanistically coherent. But CX-516 is the weakest version of that story. CX-546 has better PK. CX-614 has better receptor kinetics. If you want to run an ampakine experiment in a rodent model today, there are cleaner probes available. CX-516 retains some value as a reference compound for cross-study comparisons with older literature, but that’s a narrow use case.

What we don’t like: a compound that was the first doesn’t stay the best, and here the field moved on pretty decisively. The Phase 2 failures aren’t disqualifying for the mechanism class, but they are disqualifying for CX-516 as a serious research target. The PK liabilities aren’t a minor issue to work around; they’re the reason this compound never graduated.

Honestly, if you’re running an AMPA potentiation research program, CX-516 belongs in your comparison set and your historical context section, not in your primary experimental arm. It’s the compound that opened the door. Later ampakines walked through it. Score reflects that accurately.

Novelty: 22
Mechanism promise: 48
In-category differentiation: 20
Evidence quality: 48
Translational signal: 28
Research bench value: 38

Rationale CX-516 scores low on novelty and differentiation because it is explicitly a superseded first-generation prototype with known pharmacokinetic liabilities; the AMPA PAM mechanism itself is genuinely interesting and partially salvages the mechanism and bench scores, but Phase 2 failures across three indications hold translational signal down, and later compounds in the same class are simply better tools.

Benzoylpyrrolidine ampakine

The first ampakine to enter human clinical trials, developed at Cortex Pharmaceuticals as a mechanism prototype with limited efficacy.

Abstract

CX-516 (Ampalex; 1-(quinoxalin-6-ylcarbonyl)piperidine; CAS 154235-83-3; molecular formula C14H15N3O; molecular weight 241.29) was the first ampakine compound to enter human clinical trials, developed at Cortex Pharmaceuticals (now RespireRx Pharmaceuticals) under license from Gary Lynch and Gary Rogers at the University of California, Irvine. The compound is a benzoylpyrrolidine class AMPA receptor positive allosteric modulator. CX-516 advanced through Phase 2 trials in mild cognitive impairment, schizophrenia (cognitive symptoms), and fragile X syndrome, with mixed results that did not support advancement to Phase 3. The compound has poor pharmacokinetic properties (very short plasma half-life, approximately 1 to 2 hours, and low oral bioavailability) which limit its clinical utility despite mechanistic interest. CX-516 retains research utility as an AMPA potentiator probe but is largely superseded by later-generation compounds (CX-546, CX-614, and others). Doses in clinical trials ranged from 200 to 1200 mg per administration, three to four times daily. The compound is sold as a research chemical in jurisdictions where it is not scheduled.

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The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

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Tag: Benzoylpyrrolidine ampakine

CX-516 (Ampalex)

Abstract

Read the full monograph