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Purity: ≥98%
JNJ-42165279 is a novel, potent, covalent and selective FAAH (fatty acid amide hydrolase) inhibitor with IC50 of 70 ± 8 nM and 313 ± 28 nM for hFAAH and rFAAH, respectively. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio.
| Targets |
JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio.[1]
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| ln Vitro |
JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio.[1]
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| ln Vivo |
In the rat spinal nerve ligation (SNL or Chung) model of neuropathic pain, oral administration of JNJ-42165279 dose-dependently reversed tactile allodynia. The ED₉₀ was determined to be 22 mg/kg, which corresponded to a plasma concentration of 2.5 µM at the 30-minute post-dose time point when efficacy was measured. At a dose of 60 mg/kg p.o., the maximum reversal of allodynia (about 59% of the maximal possible effect, MPE) was observed 30 minutes after dosing, with significant efficacy maintained for at least 2 hours [1]
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| Enzyme Assay |
The ability of JNJ-42165279 to inhibit recombinant human and rat FAAH was quantified. The compound was incubated with the enzyme for 1 hour, after which the remaining enzymatic activity was measured to determine the apparent IC₅₀ values. JNJ-42165279 acts as a covalent inhibitor, and its apparent potency is dependent on the incubation time with the enzyme. Dialysis experiments indicated that the inhibition was not completely irreversible, as pretreated enzyme partially regained activity after dialysis [1]
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| Cell Assay |
JNJ-42165279 exhibited high selectivity against a panel of 50 receptors, enzymes, transporters, and ion-channels at 10 μM, at which concentration it did not produce >50% inhibition of binding to any of the targets. JNJ-42165279 also did not inhibit CYPS (1A2, 2C8, 2C9, 2C19, 2D6, 3A4) or hERG when tested at a 10 μM compound concentration.[1]
Mono-oxidation of JNJ-42165279 resulted in four metabolites, three localized to the substituted pyridine ring (M8, M10, and M11) and one localized to the piperazine linker (M14). M14 likely represents an N-oxide based on its longer retention time compared to parent. Sequential oxidations of these metabolites formed the dioxidation metabolites (M8 and M13). The dioxidation metabolite M9 was detected in human hepatocytes only.[1] |
| Animal Protocol |
JNJ-42165279 exhibited relatively rapid clearance in the course of rat pharmacokinetic experiments, manifesting as a low AUC and Cmax;55 however, sufficiently high exposures were obtainable to support preclinical animal models. In a subsequent higher dose (20 mg/kg) oral PK experiment, compound concentrations were determined both in the plasma and brain of rats . JNJ-42165279 reached a maximum plasma concentration of 4.2 μM after 1 h, falling to about 130 nM at 8 h and decreasing to below the LLQ by 16 h. [1]
The analgesic properties of JNJ-42165279 in the rat spinal nerve ligation (SNL or Chung) model of neuropathic pain were examined. Animals developed robust tactile allodynia that was dose-dependently reversed by JNJ-42165279.[1] Neuropathic Pain Model (SNL): Tactile allodynia was induced in rats by tight ligation of the L5 and L6 lumbar spinal nerves. The sensitivity of the hind paw to von Frey filaments was measured to assess allodynia. JNJ-42165279 was administered orally. For the dose-response study, various doses were tested, and efficacy was measured 30 minutes post-dose. For the time-course study, a dose of 60 mg/kg was administered, and efficacy was measured at multiple time points post-dose [1]. Pharmacokinetic/Pharmacodynamic Study: Rats were administered JNJ-42165279 orally at a dose of 20 mg/kg. The compound was formulated as a suspension in 0.5% methylcellulose. Blood plasma and brain samples were collected at various time points post-dose (e.g., 1, 2, 4, 8, 16, 24 hours) to determine compound concentrations and levels of fatty acid amides (AEA, OEA, PEA) [1] |
| ADME/Pharmacokinetics |
In vitro metabolism: In the presence of NADPH, UDPGA and GSH, incubation of JNJ-42165279 (10 µM) with liver microsomes or hepatocytes of various species (mice, rats, dogs, monkeys, and humans) resulted in the formation of various metabolites. The main biotransformation pathways included oxidative dechlorination (loss of chlorine from the pyridine ring), single oxidation of the pyridine ring or piperazine linker, continuous double oxidation, and glucuronidation of oxidative metabolites [1]. Rat pharmacokinetics: After intravenous injection of hydrochloride (2 mg/kg), its clearance rate was 60 ± 9 mL/min/kg, the steady-state volume of distribution was 2.5 ± 0.5 L/kg, the terminal half-life was 1.1 ± 0.5 h, and the AUC was 0.6 ± 0.1 h·µg/mL. After oral administration of the suspension (10 mg/kg), the peak plasma concentration was 0.5 ± 0.06 µg/mL, the AUC was 0.92 ± 0.13 h·µg/mL, the time to peak concentration was 0.50 hours, and the oral bioavailability was 32 ± 4% [1]. Brain exposure and pharmacodynamics: After oral administration of 20 mg/kg of JNJ-42165279 to rats, peak plasma and brain tissue concentrations were reached at 1 hour (4.2 µM and 6.3 µM, respectively). The peak brain tissue concentration was slightly higher than the peak plasma concentration, but the difference disappeared after 8 hours. This exposure resulted in a more than 4-fold increase in arachidonic acid ethanolamine (AEA) levels in brain tissue, which peaked at 2 hours after administration. Oleylethanolamine (OEA) and palmitoylethanolamine (PEA) levels were significantly increased (nearly 10-fold and 12-fold, respectively), peaking at 4 hours. All fatty acid amide levels returned to baseline levels within 24 hours [1]
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| Toxicity/Toxicokinetics |
In the Ames II test, the hydrolysis degradation products of JNJ-42165279 (piperazine intermediates 1 and 3-amino-4-chloropyridine) were found to be non-mutagenic [1].
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| References | |
| Additional Infomation |
JNJ-42165279 is being investigated in the clinical trial NCT02498392 (a study of the efficacy, safety, and tolerability of JNJ-42165279 in patients with major depressive disorder and anxiety). JNJ-42165279 covalently inactivates the FAAH enzyme by carbamylation of the active serine residue (Ser241). It is not a completely irreversible inhibitor, as enzyme activity can be partially restored after dialysis. The compound exhibits some hydrolytic instability in solutions at pH 2–10 and undergoes slight degradation under fluorescent irradiation in the solid state. A stable formulation was prepared by suspending the free base in 0.5% methylcellulose for preclinical and clinical studies [1]. Based on its favorable preclinical properties, JNJ-42165279 has been advanced to clinical trials for evaluation of various neurological disorders [1].
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| Molecular Formula |
C18H17CLF2N4O3
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| Molecular Weight |
410.8024
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| Exact Mass |
410.095
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| Elemental Analysis |
C, 52.63; H, 4.17; Cl, 8.63; F, 9.25; N, 13.64; O, 11.68
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| CAS # |
1346528-50-4
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| Related CAS # |
1346528-50-4;1346528-52-6 (mono HCl salt);1346528-51-5 (2HCl salt);
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| PubChem CID |
54576693
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
541.2±50.0 °C at 760 mmHg
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| Flash Point |
281.1±30.1 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.643
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| LogP |
2.84
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
28
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| Complexity |
565
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C([H])N=C([H])C=1N([H])C(N1C([H])([H])C([H])([H])N(C([H])([H])C2C([H])=C([H])C3=C(C=2[H])OC(O3)(F)F)C([H])([H])C1([H])[H])=O
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| InChi Key |
YWGYNGCRVZLMCS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H17ClF2N4O3/c19-13-3-4-22-10-14(13)23-17(26)25-7-5-24(6-8-25)11-12-1-2-15-16(9-12)28-18(20,21)27-15/h1-4,9-10H,5-8,11H2,(H,23,26)
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| Chemical Name |
N-(4-chloropyridin-3-yl)-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)piperazine-1-carboxamide
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| Synonyms |
JNJ-42165279; JNJ 42165279; JNJ42165279.
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (~243.43 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (7.30 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 30.0 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: ≥ 3 mg/mL (7.30 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 3 mg/mL (7.30 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4343 mL | 12.1714 mL | 24.3427 mL | |
| 5 mM | 0.4869 mL | 2.4343 mL | 4.8685 mL | |
| 10 mM | 0.2434 mL | 1.2171 mL | 2.4343 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 Efficacy ofJNJ-42165279in the rat SNL model of neuropathic pain.ACS Med Chem Lett. 2015 Dec 10; 6(12): 1204–1208. |
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