KML-29 is monoacylglycerol lipase inhibitor and an O-hexafluoroisopropyl carbamate analogue 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.
Physicochemical Properties
| Molecular Formula | C24H21F6NO7 |
| Molecular Weight | 549.4224 |
| Exact Mass | 549.122 |
| CAS # | 1380424-42-9 |
| Related CAS # | 1380424-42-9 |
| PubChem CID | 71656212 |
| Appearance | White to off-white solid powder |
| Density | 1.5±0.1 g/cm3 |
| Boiling Point | 554.8±50.0 °C at 760 mmHg |
| Flash Point | 289.3±30.1 °C |
| Vapour Pressure | 0.0±1.6 mmHg at 25°C |
| Index of Refraction | 1.544 |
| LogP | 6.05 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 13 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 38 |
| Complexity | 803 |
| Defined Atom Stereocenter Count | 0 |
| 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 |
| 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 |
| Synonyms | KML-29 KML29 KML 29. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | KML29 dose-dependently raises brain 2-AG levels up to ten times without changing anandamide, palmitoylethanolamide, or oleoylethanolamide levels in the brain [2]. KML29 is a strong inhibitor of the hydrolysis of 2-AG, whereas it has no effect on the hydrolysis of AEA at any tested concentration [2]. |
| ln Vivo | KML29 prevents the analgesic effect without causing adverse effects similar to cannabis [3]. The preventive effect of KML29 (20 mg/kg) against fever produced by LPS is considerable but moderate [3]. |
| Animal Protocol |
Animal/Disease Models: C57Bl/6 mice[2]. Doses: 1-40 mg/kg. Route of Administration: PO single dose. Experimental Results: Selective inhibition of MAGL in mice. Animal/Disease Models: Wistar albino male rat [2]. Doses: 20 mg/kg (+LPS E. coli O111:B4 (250 µg/kg, SC)). Management: SC. Experimental Results: Simultaneous administration of KML29 and LPS E. coli O111:B4 Dramatically diminished ΔT (Type 1 error 5%, 1.7-fold) compared to saline + LPS E. coli O111:B4. Coadministration of KML29 with LPS E. coli O111:B4 resulted in a reduction in the fever plateau compared with administration of LPS EE E. coli O111:B4 + saline. |
| References |
[1]. Discrimination between two endocannabinoids. Chem Biol. 2012 May 25;19(5):545-7. [2]. 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. [3]. 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. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~50 mg/mL (~91.01 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.55 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8201 mL | 9.1005 mL | 18.2010 mL | |
| 5 mM | 0.3640 mL | 1.8201 mL | 3.6402 mL | |
| 10 mM | 0.1820 mL | 0.9101 mL | 1.8201 mL |