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Tag: MONOGRAPH

Dihexa

Plain-language summaryIntrigue 87 / 100

Dihexa is a small molecule based on a fragment of angiotensin (a blood pressure hormone). Despite that origin, what makes it interesting is what it does in the brain: research shows it dramatically increases the formation of new connections between brain cells (synapses), with potential applications in Alzheimer disease and cognitive enhancement. Stocked in the Kodiac catalog as a research-only powder for laboratory work; not a medicine, not for human consumption.

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 Kodiac editorial, not peer-reviewed.

Our opinion on this compoundContested mechanism

52/100

Novel AT4 peptidomimetic with gutted evidence base after 2025 JPET retractions and failed clinical program

Look, the Dihexa story is one of the more spectacular collapses in recent CNS research, and it’s worth understanding what actually happened before deciding whether the compound has any remaining bench value.

The foundational papers, four JPET publications from the Harding lab at WSU between 2011 and 2014, were retracted in April 2025 following confirmed Western blot manipulation: band splicing and duplication across distinct experimental conditions. Those papers underwrote Athira Pharma, a $204 million IPO, and the clinical program that followed. The clinical lead, fosgonimeton (ATH-1017), failed to meet primary endpoints in both the LIFT-AD Phase 2/3 trial in mild-to-moderate Alzheimer disease and the SHAPE Phase 2 trial in dementia with Lewy bodies. A DOJ False Claims Act settlement landed in January 2025 for $4.07 million. The HGF/c-Met mechanism hypothesis that powered all of this is now scientifically untenable in its original form.

So what’s left? Honestly, more than nothing. Behavioral data from Morris water maze and novel object recognition paradigms that doesn’t depend on Western blot immunochemistry hasn’t been retracted. Electrophysiology work showing LTP facilitation in hippocampal slice preparations remains in the record. Synaptogenesis data from microscopy-based assays is similarly intact. These arent nothing: they suggest the compound does something pharmacologically active in the CNS, even if the original mechanistic story is gone.

The AT4 receptor / IRAP (insulin-regulated aminopeptidase) angle is the current best hypothesis for what Dihexa is actually doing. AT4-class pharmacology is genuinely understudied, and Dihexa’s profile as a small, orally active, BBB-penetrant peptidomimetic with picomolar activity in behavioral models is still unusual chemistry. There aren’t many compounds with those combined properties in this space, retracted mechanism or not. As an N-hexanoic-Tyr-Ile analog, it sits in a chemical class that has essentially no other well-characterized members at the CNS level.

We think the appropriate posture for bench investigators is to treat the HGF/c-Met story as dead, skip the Western blot replication attempts, and focus instead on what the compound does in electrophysiology and behavioral models relative to other AT4-class probes. The novelty and differentiation scores here are real: unusual chemistry, no close competitors in its niche. The evidence and translational scores are gutted because the clinical program failed and the core mechanistic papers are gone. That’s what a 52 looks like for a compound: genuinely interesting bench chemistry wrapped in a thoroughly compromised evidentiary record. Source it carefully, verify by HPLC, and treat the retracted literature as background context rather than foundation.

Novelty

70

Mechanism promise

50

In-category differentiation

70

Evidence quality

28

Translational signal

25

Research bench value

58

Rationale High novelty and differentiation scores survive intact because the compound’s AT4-derived peptidomimetic chemistry is genuinely unusual and uncontested; evidence and translational axes are severely depressed by the April 2025 JPET retractions of all four foundational HGF/c-Met papers and the failed fosgonimeton Phase 2/3 program, consistent with the spec’s explicit Dihexa callout targeting overall 52-58.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

Angiotensin IV analog (procognitive small peptidomimetic)

A small angiotensin IV analog with a contested mechanism of action, a high-profile commercialization failure, and a literature record selectively retracted in 2025.

Abstract

Dihexa, also known as PNB-0408 and N-hexanoic-Tyr-Ile-(6) amino-hexanoic amide, is a hexapeptide-derived small molecule developed in the Harding laboratory at Washington State University as a procognitive analog of angiotensin IV. It was foundationally hypothesized to act through agonism of the hepatocyte growth factor (HGF) / c-Met receptor system, a mechanism that promised oral bioavailability, blood-brain barrier penetration at picomolar potency, and rapid synaptogenesis in cortical and hippocampal neurons. Between 2011 and 2014, four peer-reviewed publications established the compound’s commercial pipeline and underwrote the formation of Athira Pharma, a publicly traded biotechnology firm that raised over 204 million dollars in a 2020 initial public offering. Each of these four publications was retracted by the Journal of Pharmacology and Experimental Therapeutics in April 2025 following findings of academic misconduct, specifically the splicing and duplication of Western blot bands across distinct experimental conditions. The Department of Justice settled a False Claims Act qui tam action against Athira Pharma in January 2025 for 4.07 million dollars. The clinical lead derived from this program, fosgonimeton (ATH-1017, NDX-1017), failed to meet primary endpoints in the LIFT-AD Phase 2/3 trial in mild-to-moderate Alzheimer disease and the SHAPE Phase 2 trial in dementia with Lewy bodies. This monograph reviews what is now established about Dihexa’s chemistry, pharmacokinetics, behavioral effects, and clinical record, separating the verified record from the retracted, and provides sourcing, identity verification, reconstitution, and handling guidance for in vitro and in vivo investigative work.

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.

May 8, 2026
5-Amino-1MQ

Plain-language summaryIntrigue 72 / 100

5-Amino-1MQ is a small molecule that selectively inhibits the NNMT enzyme. NNMT degrades NAD+ precursors and methyl donors; inhibiting it boosts cellular energy and fat metabolism, with research interest in obesity and metabolic disease. Capsule format here. Stocked in the Kodiac catalog as a research-only powder for laboratory work; not a medicine, not for human consumption.

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

Our opinion on this compoundNovel, promising

59/100

Novel NNMT inhibitor with elegant dual-node mechanism and solid preclinical case, human evidence still absent

Yeah, 5-Amino-1MQ is one of the more interesting small molecules to come out of academic medicinal chemistry in the last decade. The target, nicotinamide N-methyltransferase, had been a curiosity in cancer biology for years before anyone asked whether selective inhibition might be pharmacologically useful outside the oncology context. What changed is a pair of mechanistic insights that make NNMT genuinely interesting for metabolic and aging research: the enzyme simultaneously drains nicotinamide away from the NAD+ salvage pathway and consumes SAM, the universal methyl donor. Block NNMT and you potentially shift both the cellular NAD+ pool and methylation potential in the same direction. Thats the kind of elegant dual-node mechanism that gets bench scientists interested, and it’s distinct enough from standard NAD+ precursor supplementation to justify its own research program.

The evidence base is real but you have to be honest about what it consists of. Most of it is academic rodent work, primarily adipose and skeletal muscle stem cell models. The obesity model data from the Jacobson group and related labs is reasonably well-replicated at the preclinical level, with consistent effects on body composition, adipocyte size, and metabolic markers in diet-induced obesity models. The skeletal muscle stem cell aging angle is genuinely interesting and addresses a different biology than the adipose story. The trouble is there’s essentially no human data. No IND, no phase 1 safety signal to anchor on, no pharmacokinetic data in people to confirm that the rodent predictions hold under the real constraints of human metabolism.

What we like here is that 5-Amino-1MQ is the reference compound for NNMT biology full stop. If you’re studying this target in cancer, adipose, or aging contexts, this is the tool you reach for. There isn’t a cleaner or better-characterized selective inhibitor available for in vitro or in vivo work, which gives it real bench utility that extends beyond its own pharmacological story into any program touching NAD+ biology or one-carbon metabolism.

What we dont like is the evidence maturity problem. The research record is short, the human signal is absent, and there’s a real open question about how well the rodent adipose phenotype translates. The SAM depletion axis hasn’t been fully characterized for off-target methylation effects under prolonged dosing, and that gap matters when you’re talking about a compound that touches the universal methyl donor. Until there’s more replication across independent labs and some pharmacokinetic anchoring in humans, this stays in the promising preclinical bucket.

The score lands at 59 because the target and mechanism are genuinely novel, the preclinical case is credible, and the bench utility is real, but the translational gap is wide enough that you cant call it more than that. For investigators studying NAD+ biology, adipose metabolism, or muscle stem cell aging, 5-Amino-1MQ is probably already on your list. For everyone else, worth knowing about but premature to center a research program around.

Novelty

68

Mechanism promise

72

In-category differentiation

68

Evidence quality

38

Translational signal

38

Research bench value

60

Rationale Scores well on novelty and mechanism because NNMT inhibition with dual NAD+/SAM connectivity is a genuinely recent and elegant target, and 5-Amino-1MQ is the field reference compound; evidence quality and translational signal are pulled down significantly by the short research record and total absence of human pharmacokinetic or efficacy data.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

Small-molecule selective NNMT inhibitor (capsule format)

A 159 Da quinolinium small molecule that selectively inhibits nicotinamide N-methyltransferase, characterized for effects on adipose metabolism and skeletal muscle stem cell function. Supplied as 60 capsules x 50 mg.

Abstract

5-Amino-1-methylquinolinium iodide (5-Amino-1MQ; CAS 954126-98-8; molecular formula C11H12N2; molecular weight 159.20 for the cation; the iodide salt has additional mass) is a small-molecule selective inhibitor of nicotinamide N-methyltransferase (NNMT, EC 2.1.1.1), the enzyme that methylates nicotinamide to N1-methylnicotinamide using S-adenosylmethionine (SAM) as the methyl donor. NNMT activity diverts nicotinamide away from the NAD+ salvage pathway and consumes SAM, which connects NNMT activity to both the cellular NAD+ pool and the methylation potential of the cell. NNMT is overexpressed in many cancers (where it has been characterized as an “oncometabolic” enzyme) and in obesity-associated white adipose tissue, where it has been linked to insulin resistance and to the metabolic dysfunction phenotype. Selective NNMT inhibitors including 5-Amino-1MQ have been developed primarily by academic medicinal chemistry groups beginning in the late 2010s and have been characterized in cell culture, in vivo rodent obesity and aging models, and in skeletal muscle stem cell and aging models. The compound is supplied at Kodiac biolabs as a 60-capsule oral preparation, 50 milligrams per capsule, reflecting the small molecule’s stability and oral bioavailability. There is no FDA-approved IND for 5-Amino-1MQ in any indication. The compound is not a regulated drug substance in the United States, the European Union, or Japan. The principal limitations on the strength of the evidence are the relatively short duration of the published research record and the limited human safety and efficacy data.

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.

KDC-MN-014Open in new tab →

Download PDF →

Acquire 5-Amino-1MQ from the catalog

View 5-Amino-1MQ →

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.

May 8, 2026

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