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Purity: ≥98%
JNJ-63533054, a glycine benzamide analog, is a potent, selective and brain penetrant agonist of hGPR139 (human G-protein-coupled receptors) with an EC50 of 16 nM. It was found during a targeted high throughput screening for GPR139 that was carried out for a chosen 100K compounds. Following further examination and research on the structure-activity relationship, (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide, also known as JNJ-63533054, was found to be a strong and specific agonist of hGPR139, with an EC50 of 16 nM. JNJ-63533054 was found to cross the blood-brain barrier and have good drug-like properties amenable for oral dosing in rat.
| Targets |
human GPR139 ( Ki = 0.024 μM ); mouse GPR139 ( Ki = 0.054 μM ); rat GPR13 ( Ki = 0.075 μM )
JNJ-63533054 specially induces human GPR139 in the calcium mobilization (EC50 = 16 ± 6 nM) and GTPγS binding (EC50 = 17 ± 4 nM) assays. JNJ-63533054 exhibits comparable potency in activating the GPR139 receptors in rats and mice (rat EC50 = 63 ± 24 nM, mouse EC50 = 28 ± 7 nM)[1]. |
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| ln Vitro |
JNJ-63533054 specially induces human GPR139 in the calcium mobilization (EC50 = 16 ± 6 nM) and GTPγS binding (EC50 = 17 ± 4 nM) assays. JNJ-63533054 exhibits comparable potency in activating the GPR139 receptors in rats and mice (rat EC50 = 63 ± 24 nM, mouse EC50 = 28 ± 7 nM)[1].
JNJ-63533054 acts as a potent and selective agonist for the human GPR139 receptor with an EC₅₀ of 16 nM and maximal efficacy (Eₘₐₓ) of 138% relative to L-Trp. It showed no significant activity at rat GPR142, confirming selectivity for GPR139. The compound exhibited good specific binding in CHO-TRex cells stably expressing human GPR139, as demonstrated in radioligand binding assays using [³H]-7c. It displayed no cross-reactivity in a panel of 50 GPCRs, ion channels, and transporters. The compound also showed high solubility (>35 µM) at pH 2 and pH 7, and no CYP450 inhibition was observed. In MDCK permeability assays, it showed good cellular permeability with a low efflux ratio (1.7). Plasma protein binding was low in both human and rat (free fraction 10% and 25%, respectively). Brain tissue binding in rat showed a free fraction of 9%. [2] |
| ln Vivo |
According to the results of an external selectivity panel comprising 50 known GPCRs, ion channels, and transporters, the small-molecule JNJ-63533054 exhibits no cross-reactivity and has appropriate pharmacokinetic characteristics for in vivo investigations. JNJ-63533054, when administered orally to rats, crosses the blood-brain barrier and reaches exposure in the micromolar range. JNJ-63533054 administration reduces rats' spontaneous locomotor activity[1].
After oral administration in rats (5 mg/kg), JNJ-63533054 achieved good systemic exposure with a Cₘₐₓ of 317 ng/mL (~1 µM) and an AUC of 683 h·ng/mL. The compound effectively crossed the blood-brain barrier with a brain-to-plasma ratio (b/p) of 1.2. It showed an oral bioavailability of 49% in rats. [2] |
| Enzyme Assay |
The GPR139 functional assay used CHO-TRex cells stably expressing human GPR139.
Calcium flux was measured as an indicator of receptor activation. The EC₅₀ values were determined from dose-response curves generated from at least three independent experiments. The maximal response (Eₘₐₓ) was normalized to that of L-Trp (set as 100%). [2] |
| Cell Assay |
CHO-TRex cells stably expressing human GPR139 were used for functional calcium mobilization assays.
Cells were loaded with a calcium-sensitive fluorescent dye and stimulated with increasing concentrations of the test compound. Fluorescence was measured using a fluorometric imaging plate reader (FLIPR). Data were analyzed to calculate EC₅₀ and Eₘₐₓ values. For selectivity screening, the compound was tested against a panel of 50 GPCRs, ion channels, and transporters in whole-cell assays. [2] |
| Animal Protocol |
Male Sprague-Dawley rats (350-450 g)[1]
3 mg/kg, 10 mg/kg, and 30 mg/kg
Oral administration; once
Pharmacokinetic studies were conducted in rats. For intravenous administration, the compound was dosed at 1 mg/kg. For oral administration, the compound was dosed at 5 mg/kg via oral gavage. Blood and brain samples were collected at various time points post-dosing. Plasma and brain concentrations were determined using LC-MS/MS. Pharmacokinetic parameters including clearance, volume of distribution, half-life, Cₘₐₓ, AUC, and brain-to-plasma ratio were calculated. [2] |
| ADME/Pharmacokinetics |
The extraction rate was 0.3% in human liver microsomes. The extraction rate was 0.4% in rat liver microsomes. The MDCK permeability (Pₐₚₚ) was 32 × 10⁻⁶ cm/s. The human plasma protein binding rate was 90%, and that of rats was 75% (free fractions of 10% and 25%, respectively). The binding rate of rat brain tissue was 91% (free fraction of 9%). The oral bioavailability in rats was 49%. The systemic clearance rate in rats was 53 mL/min/kg. The steady-state volume of distribution (Vₛₛ) was 2.1 L/kg. The rat half-life (t₁/₂) was 2.5 hours. The rat brain-plasma ratio (b/p) was 1.2. [2]
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| References |
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| Additional Infomation |
JNJ-63533054 is a glycine benzamide derivative identified through high-throughput screening and structure-activity relationship optimization. It is a selective GPR139 agonist with good central nervous system penetration, making it a useful tool compound for studying the pharmacology of GPR139 in the brain. A tritium-labeled version ([³H]-7c) was synthesized for binding and occupancy studies. This compound is also known as (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide. [2]
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| Molecular Formula |
C17H17CLN2O2
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| Molecular Weight |
316.79
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| Exact Mass |
316.097
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| Elemental Analysis |
C, 64.46; H, 5.41; Cl, 11.19; N, 8.84; O, 10.10
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| CAS # |
1802326-66-4
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| Related CAS # |
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| PubChem CID |
2548547
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
559.7±45.0 °C at 760 mmHg
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| Flash Point |
292.3±28.7 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.586
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| LogP |
3.13
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
22
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| Complexity |
383
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1=C([H])C([H])=C([H])C(=C1[H])C(N([H])C([H])([H])C(N([H])[C@@]([H])(C([H])([H])[H])C1C([H])=C([H])C([H])=C([H])C=1[H])=O)=O
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| InChi Key |
MWDVCHRYCKXEBY-LBPRGKRZSA-N
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| InChi Code |
InChI=1S/C17H17ClN2O2/c1-12(13-6-3-2-4-7-13)20-16(21)11-19-17(22)14-8-5-9-15(18)10-14/h2-10,12H,11H2,1H3,(H,19,22)(H,20,21)/t12-/m0/s1
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| Chemical Name |
3-chloro-N-[2-oxo-2-[[(1S)-1-phenylethyl]amino]ethyl]benzamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.89 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 (7.89 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 | 3.1567 mL | 15.7833 mL | 31.5667 mL | |
| 5 mM | 0.6313 mL | 3.1567 mL | 6.3133 mL | |
| 10 mM | 0.3157 mL | 1.5783 mL | 3.1567 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.
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High Throughput Screening Lead and Initial Optimization.ACS Med Chem Lett.2015 Jul 20;6(9):1015-8. |
Structure of GPR139 agonists.ACS Med Chem Lett.2015 Jul 20;6(9):1015-8. |
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