RESEARCH MONOGRAPH · KDC-MN-331

KML29

May 9, 2026 Kodiac biolabs Research Revised May 30, 2026 2 min read

Our opinion on this compound

69/100

Cleaner second-generation MAGL inhibitor, the right choice when you actually want MAGL selectivity

KML29 is the cleanup-act for JZL184. Cravatt's group developed it specifically to address the FAAH cross-reactivity problem in JZL184, and the result is a meaningfully better selectivity profile: roughly 4000-fold MAGL over FAAH selectivity, which means you can dose to full MAGL inhibition without confounding the anandamide arm of endocannabinoid signaling.

Mechanism: irreversible MAGL inhibitor, urea-based covalent chemistry similar to JZL184 but with better off-target profile, oral bioavailability is good, brain penetration is solid, IC50 in the low-nM range. The 2-AG elevation phenotype is similar to JZL184 (eight to ten fold) but the FAAH baseline stays clean, so you can pair it with a separate FAAH inhibitor like PF-04457845 to dial in the desired endocannabinoid pharmacology.

The Long-Niphakis paper and the followup chronic-dosing characterization work is the right reading list. Schlosburg's chronic studies showed the same CB1 downregulation phenotype as JZL184 (its a real biology of sustained 2-AG signaling, not a drug-specific artifact), so the chronic-dosing caveat persists for any MAGL inhibitor.

For research KML29 is the better tool for most modern questions. The selectivity makes interpretation cleaner, the PK is good, and the in vivo behavioral phenotype is well-characterized. It's particularly useful in pain research where the 2-AG arm of endocannabinoid signaling is mechanistically interesting, and in neuroinflammation work where both anandamide and 2-AG contribute differently to glial signaling.

Sourcing: research-grade KML29 is available but less ubiquitously than JZL184, and the price per mg is meaningfully higher. HPLC verification is essential, the urea chemistry is more sensitive than the simpler carbamates and lot-to-lot variability can show up in the degradant profile. Storage should be desiccated and dark.

What we like: clean MAGL selectivity for the first time in the class, good PK, useful for combination experiments with selective FAAH inhibitors, well-validated by independent groups.

What we dont like: cost compared to JZL184, the chronic-dosing tolerance issue is inherent to the target and not solvable pharmacologically, and the compound is essentially research-only with no clinical development that we know of (the broader MAGL-clinical effort has been slow).

If you're serious about MAGL pharmacology in 2025, this is the tool. JZL184 is for legacy comparisons.

Evidence: 60
Mechanism: 85
Reliability: 78
Safety: 75
Sourcing: 65
Value: 60
Signal: 60
Staying power: 65

Plain-language summary Intrigue 48 / 100

KML29 is the second-generation cleanup of JZL184 from the same Cravatt laboratory, with about 4000-fold selectivity for MAGL over FAAH instead of the 300-fold of its predecessor. That extra cleanliness matters for research because it lets investigators raise endogenous 2-AG without simultaneously raising anandamide, isolating the contribution of each endocannabinoid. It is used purely as a research tool to study MAGL biology in pain, inflammation, and neurodegeneration, and has not been advanced to clinical trials. 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.

Selective MAGL inhibitor (second-generation)

A second-generation covalent MAGL inhibitor with improved selectivity over FAAH.

Abstract

KML29 (CAS 1366507-82-3; molecular formula C27H24F4N2O4; molecular weight 516.49) is a second-generation covalent MAGL inhibitor developed by Cravatt and colleagues. The compound has improved selectivity for MAGL over FAAH (greater than 4000-fold) compared to JZL184 (300-fold), reducing the off-target FAAH inhibition that complicated interpretation of some JZL184 studies. Mechanism is the same as JZL184: irreversible carbamoylation of MAGL's active-site serine. Used in academic research where clean MAGL inhibition without FAAH crossover is required. No human clinical development.

Mechanism of action

Covalent MAGL inhibitor; approximately 4000-fold MAGL/FAAH selectivity. Cleaner research tool than JZL184 for selective 2-AG elevation.

Reported research dose ranges

Rodent research 5 to 40 mg/kg intraperitoneal.

References

Chang JW, et al. Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates. Chem Biol 2012.
Niphakis MJ, et al. Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors. ACS Chem Neurosci 2013.
Mulvihill MM, Nomura DK. Therapeutic potential of monoacylglycerol lipase inhibitors. Life Sci 2013.

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The full reference document is available as a research-use-only PDF download. Note: PDFs for newly added compounds may take a few hours to propagate after this article was published.

KDC-MN-331

The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.

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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.

Kodiac sells research compounds for investigative use only.

KML29

Abstract

Mechanism of action

Reported research dose ranges

References

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Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

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