Org-26576 – Kodiac biolabs

Plain-language summaryIntrigue 40 / 100

Org-26576 is a sulfonamide AMPA potentiator developed at Organon. Phase 2 trials investigated it in major depressive disorder and ADHD. 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 Kodiac editorial, not peer-reviewed.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 compoundNiche research probe

39/100

Discontinued Merck ampakine with modest Phase 2 signal and limited bench accessibility

AMPA receptor positive allosteric modulators have a genuinely compelling theoretical basis. By slowing channel deactivation and desensitization, they amplify glutamatergic throughput, drive BDNF expression, and modulate synaptic plasticity in ways that NMDA-targeted compounds simply can’t replicate. The mechanism is interesting, the rationale for depression and cognitive enhancement is plausible, and Org-26576 at least made it further through clinical development than most ampakines. Organon built the program, Schering-Plough inherited it, Merck finished it, and then walked away. That arc matters.

Here’s the thing about the AMPA PAM class: it has a long, frustrating history of preclinical promise colliding with clinical disappointment. CX516, CX717, farampator, LY404187 and a dozen others all generated real excitement in the late 1990s through mid-2000s, showed plausible Phase 1 tolerability, and then produced Phase 2 data described in almost identical language to whats in Org-26576’s dossier: modest cognitive endpoint improvements, no adverse signal. In pharmaceutical development that’s a polite way of saying the delta wasn’t there. When a well-resourced pharma group has already invested in full IND-enabling studies and a Phase 2 execution and still walks away, the independent research community is left with a thin published evidence base and whatever can be reconstructed from conference abstracts.

The sulfonamide scaffold is a genuine chemical differentiator. Org-26576 is not just a CX-class analog; the sulfone headgroup changes the binding geometry and potentially the kinetic profile of AMPA channel modulation in ways that aren’t fully worked out in the public literature. For a group specifically investigating structure-activity relationships across AMPA PAM chemotypes, or trying to understand whether kinetic selectivity differences between ampakine classes have functional consequences, this compound represents a well-defined clinical-stage data point. It cleared human safety. That’s real. It’s also about the extent of the positive case.

Sourcing is a serious obstacle. The compound is rarely available in research-chemical-grade markets, which means bench accessibility is low and reproducibility across labs is essentially hypothetical. Researchers who want an AMPA PAM probe with documented methodology would typically reach for farampator, which has more published protocol support, or look at the newer BNT-III class compounds generating current literature. We think the under-characterized sulfonamide angle is the only genuine hook here, and it’s a narrow one.

Honestly, this scores where it does because the class is mature, the clinical outcome was modest, the compound is hard to source, and the evidence base is largely gated behind Merck’s development files. Interesting chemistry in an underdelivering class isnt the same as a compelling research target.

Novelty: 38
Mechanism promise: 57
In-category differentiation: 30
Evidence quality: 40
Translational signal: 35
Research bench value: 28

Rationale Org-26576 earns modest scores across the board: the sulfonamide AMPA PAM scaffold has chemical interest but the class has a consistent history of clinical underdelivery, and Merck’s discontinuation leaves the evidence base thin and sourcing nearly nonexistent for independent labs. Mechanism score is the brightest spot; differentiation and bench value are both dragged down by limited availability and a crowded class where better-characterized probes already exist.

Sulfonamide AMPA potentiator

An Organon/Merck ampakine that reached Phase 2 in major depressive disorder.

Abstract

Org-26576 is a sulfonamide-class AMPA receptor positive allosteric modulator developed by Organon (subsequently Schering-Plough, Merck) for cognitive enhancement in major depressive disorder and other indications. The compound advanced through Phase 2 trials with results consistent with the ampakine class profile (modest cognitive endpoint improvements, no adverse signal). The development program was discontinued under Merck. Pharmacokinetics: plasma half-life approximately 5 hours; oral bioavailability adequate. The compound is rarely available in research-chemical-grade markets.

Read the full monograph

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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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.