KML-29 | CAS#1380424-42-9 | MAGL inhibitor

MedKoo Cat#: 555190 | Name: KML-29

Description:

WARNING: This product is for research use only, not for human or veterinary use.

KML-29 is monoacylglycerol lipase inhibitor and an O-hexafluoroisopropyl carbamate analog of JZL 184. KML-29 potently and selectively inhibits MAGL (IC50s = 15, 43, and 5.9 nM in mouse, rat, and human brain proteomes, respectively). KML29 with gabapentin synergistically produces analgesia in mice.

Chemical Structure

KML-29

CAS#1380424-42-9

Theoretical Analysis

MedKoo Cat#: 555190

Name: KML-29

CAS#: 1380424-42-9

Chemical Formula: C24H21F6NO7

Exact Mass: 549.1222

Molecular Weight: 549.42

Elemental Analysis: C, 52.47; H, 3.85; F, 20.75; N, 2.55; O, 20.38

Price and Availability

Size	Price	Availability
100mg	USD 750.00	2 weeks
200mg	USD 1,200.00	2 weeks
500mg	USD 2,400.00	2 weeks
1g	USD 3,850.00	2 weeks
2g	USD 5,650.00	2 weeks

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Related CAS #

No Data

Synonym

KML-29; KML29; KML 29.

IUPAC/Chemical Name

1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate

InChi Key

SXHQLPHDBLTFPM-UHFFFAOYSA-N

InChi Code

InChI=1S/C24H21F6NO7/c25-23(26,27)20(24(28,29)30)38-21(32)31-7-5-13(6-8-31)22(33,14-1-3-16-18(9-14)36-11-34-16)15-2-4-17-19(10-15)37-12-35-17/h1-4,9-10,13,20,33H,5-8,11-12H2

SMILES Code

O=C(N1CCC(C(C2=CC=C(OCO3)C3=C2)(C4=CC=C(OCO5)C5=C4)O)CC1)OC(C(F)(F)F)C(F)(F)F

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Endocannabinoids such as 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide are biologically active lipids that are involved in a number of synaptic processes including activation of cannabinoid receptors. Monoacylglycerol lipase (MAGL) is a serine hydrolase responsible for the hydrolysis of 2-AG to arachidonic acid and glycerol, thus terminating its biological function.

Product Data

Product Data

Instruction

View handling instruction

Biological target:

KML29 is an extremely selective, orally active and irreversible MAGL inhibitor, with IC50 values of 15 nM, 43 nM and 5.9 nM for mouse, rat and human MAGL, respectively.

In vitro activity:

The resulting model provided evidence that the HFIP group of KML29 could bind to MAGL in a similar manner to that predicted for the glycerol moiety of 2-AG (Bertrand et al., 2010) including potential interactions with the conserved active site residues His121 and Tyr194 (Figure 2C). Reference: Chem Biol. 2012 May 25;19(5):579-88. https://pubmed.ncbi.nlm.nih.gov/22542104/

In vivo activity:

KML29 attenuated carrageenan-induced murine paw oedema and completely reversed carrageenan-induced mechanical allodynia. These results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects. Referece: Br J Pharmacol. 2014 Mar;171(6):1392-407. https://pubmed.ncbi.nlm.nih.gov/23848221/

	Solvent	mg/mL	mM
Solubility
	DMSO	35.7	64.88

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 549.42 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Rojo-Bustamante E, Íñigo-Marco I, Abellanas MA, Vinueza-Gavilanes R, Baltanás A, Luquin E, Arrasate M, Aymerich MS. CB2 Receptors and Neuron-Glia Interactions Modulate Neurotoxicity Generated by MAGL Inhibition. Biomolecules. 2020 Aug 18;10(8):1198. doi: 10.3390/biom10081198. PMID: 32824740; PMCID: PMC7464766. 2. Chang JW, Niphakis MJ, Lum KM, Cognetta AB 3rd, Wang C, Matthews ML, Niessen S, Buczynski MW, Parsons LH, Cravatt BF. Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates. Chem Biol. 2012 May 25;19(5):579-88. doi: 10.1016/j.chembiol.2012.03.009. Epub 2012 Apr 26. PMID: 22542104; PMCID: PMC3361572. 3. Colangeli R, Morena M, Werner A, Thompson RJ, van der Stelt M, Pittman QJ, Hill MN, Teskey GC. 2-AG-mediated Control of GABAergic Signaling is Impaired in a Model of Epilepsy. J Neurosci. 2022 Dec 1:JN-RM-0541-22. doi: 10.1523/JNEUROSCI.0541-22.2022. Epub ahead of print. PMID: 36460464. 4. Ignatowska-Jankowska BM, Ghosh S, Crowe MS, Kinsey SG, Niphakis MJ, Abdullah RA, Tao Q, O' Neal ST, Walentiny DM, Wiley JL, Cravatt BF, Lichtman AH. In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. Br J Pharmacol. 2014 Mar;171(6):1392-407. doi: 10.1111/bph.12298. PMID: 23848221; PMCID: PMC3954480.

In vitro protocol:

In vivo protocol:

1. Colangeli R, Morena M, Werner A, Thompson RJ, van der Stelt M, Pittman QJ, Hill MN, Teskey GC. 2-AG-mediated Control of GABAergic Signaling is Impaired in a Model of Epilepsy. J Neurosci. 2022 Dec 1:JN-RM-0541-22. doi: 10.1523/JNEUROSCI.0541-22.2022. Epub ahead of print. PMID: 36460464. 2. Ignatowska-Jankowska BM, Ghosh S, Crowe MS, Kinsey SG, Niphakis MJ, Abdullah RA, Tao Q, O' Neal ST, Walentiny DM, Wiley JL, Cravatt BF, Lichtman AH. In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. Br J Pharmacol. 2014 Mar;171(6):1392-407. doi: 10.1111/bph.12298. PMID: 23848221; PMCID: PMC3954480.

1: Crowe MS, Wilson CD, Leishman E, Prather PL, Bradshaw HB, Banks ML, Kinsey SG. The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice. Br J Pharmacol. 2017 Dec;174(23):4523-4539. doi: 10.1111/bph.14055. Epub 2017 Nov 20. PubMed PMID: 28963716; PubMed Central PMCID: PMC5715597. 2: Pasquarelli N, Porazik C, Bayer H, Buck E, Schildknecht S, Weydt P, Witting A, Ferger B. Contrasting effects of selective MAGL and FAAH inhibition on dopamine depletion and GDNF expression in a chronic MPTP mouse model of Parkinson's disease. Neurochem Int. 2017 Nov;110:14-24. doi: 10.1016/j.neuint.2017.08.003. Epub 2017 Aug 5. PubMed PMID: 28826718. 3: Pasquarelli N, Engelskirchen M, Hanselmann J, Endres S, Porazik C, Bayer H, Buck E, Karsak M, Weydt P, Ferger B, Witting A. Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS. Neuropharmacology. 2017 Sep 15;124:157-169. doi: 10.1016/j.neuropharm.2017.03.037. Epub 2017 Mar 31. PubMed PMID: 28373073. 4: Morena M, Leitl KD, Vecchiarelli HA, Gray JM, Campolongo P, Hill MN. Emotional arousal state influences the ability of amygdalar endocannabinoid signaling to modulate anxiety. Neuropharmacology. 2016 Dec;111:59-69. doi: 10.1016/j.neuropharm.2016.08.020. Epub 2016 Aug 20. PubMed PMID: 27553121. 5: Miller S, Leishman E, Hu SS, Elghouche A, Daily L, Murataeva N, Bradshaw H, Straiker A. Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model. Invest Ophthalmol Vis Sci. 2016 Jun 1;57(7):3287-96. doi: 10.1167/iovs.16-19356. PubMed PMID: 27333182; PubMed Central PMCID: PMC4961057. 6: Subbanna S, Psychoyos D, Xie S, Basavarajappa BS. Postnatal ethanol exposure alters levels of 2-arachidonylglycerol-metabolizing enzymes and pharmacological inhibition of monoacylglycerol lipase does not cause neurodegeneration in neonatal mice. J Neurochem. 2015 Jul;134(2):276-87. doi: 10.1111/jnc.13120. Epub 2015 Apr 30. PubMed PMID: 25857698; PubMed Central PMCID: PMC4490952. 7: Pasquarelli N, Porazik C, Hanselmann J, Weydt P, Ferger B, Witting A. Comparative biochemical characterization of the monoacylglycerol lipase inhibitor KML29 in brain, spinal cord, liver, spleen, fat and muscle tissue. Neuropharmacology. 2015 Apr;91:148-56. doi: 10.1016/j.neuropharm.2014.12.001. Epub 2014 Dec 12. PubMed PMID: 25497453. 8: Ignatowska-Jankowska BM, Ghosh S, Crowe MS, Kinsey SG, Niphakis MJ, Abdullah RA, Tao Q, O' Neal ST, Walentiny DM, Wiley JL, Cravatt BF, Lichtman AH. In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. Br J Pharmacol. 2014 Mar;171(6):1392-407. doi: 10.1111/bph.12298. PubMed PMID: 23848221; PubMed Central PMCID: PMC3954480.