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Purity: ≥98%
AM-0902 is a novel, potent and selective Transient Receptor Potential A1 (TRPA1) antagonist with IC50s of 71 and 131 nM for rTRPA1 and hTRPA1, respectively. AM-0902 demonstrated dose-dependent inhibition of AITC-induced flinching in rats, validating its utility as a tool for interrogating the role of TRPA1 in in vivo pain models.
| Targets |
Transient Receptor Potential A1 (TRPA1)
Potent antagonist of rat TRPA1 (IC50 = 0.071 µM in FLIPR assay; IC50 = 0.071 µM in ⁴⁵Ca²⁺ flux assay) and human TRPA1 (IC50 = 0.041 µM in FLIPR assay; IC50 = 0.131 µM in ⁴⁵Ca²⁺ flux assay). Selectivity over other TRP channels: No activity observed against human TRPV1 or TRPV4, or rat TRPV1, TRPV3, or TRPM8 at concentrations up to 10 µM. [1] |
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| ln Vitro |
IC50 values for rTRPA1 and hTRPA1 of AM-0902, a strong and selective TRPA1 antagonist, are 71 and 131 nM, respectively. With an average Papp of 44.5 μcm/s in MDCK cells, AM-0902 is highly permeable. It also shows strong solubility (PBS pH 7.4: 226 μM, SIF: 248 μM) and is unlikely to be a substrate for P-gp (efflux ratio = 1.3 in P-gp overexpressing MDCK cells). At doses up to 10 μM, AM-0902 showed no action against rat TRPV1, TRPV3, or TRPM8, nor against human TRPV1 or TRPV4. This indicates that AM-0902 has strong selectivity over other TRP channels. With an IC50 of 0.019 μM, AM-0902 decreases 45Ca2+ flow subsequent to rat TRPA1 activation with methylglyoxal[1].
In a FLIPR Ca²⁺ imaging assay, AM-0902 (Compound 27) demonstrated potent inhibition of both rat and human TRPA1 channels upon activation with AITC. In a ⁴⁵Ca²⁺ flux assay, it confirmed potent antagonism with rat TRPA1 IC50 of 0.071 µM and human TRPA1 IC50 of 0.131 µM. It inhibited rat TRPA1 activation by the endogenous agonist methylglyoxal with an IC50 of 0.019 µM in the ⁴⁵Ca²⁺ flux assay. It also inhibited rat TRPA1 activation induced by changes in osmolarity (hypotonic buffer), which may mimic mechanical activation, with an IC50 of 0.010 µM in the ⁴⁵Ca²⁺ flux assay. In a CEREP panel of 40 targets at 10 µM, AM-0902 (Compound 27) showed little to no inhibition (>77% POC against all targets). It exhibited only 10% block of Naᵥ1.7 channels in mouse DRG neurons at 10 µM. No agonist activity (EC50) was detected for rat or human TRPA1 in the ⁴⁵Ca²⁺ flux assay at concentrations up to >40 µM. [1] |
| ln Vivo |
In vivo, AM-0902 is a strong and specific antagonist of TRPA1. Rats (t1/2=0.6 hours and 2.8 hours for rat (0.5 mg/kg, IV), rat (30 mg/kg, PO)) have a moderate terminal elimination half-life for AM-0902. AM-0902 was found to reduce allyl isothiocyanate (AITC)-induced withdrawal in a dose-dependent manner; withdrawal was significantly reduced following dosages of 10 and 30 mg/kg. For 1, 3, 10, and 30 mg/kg doses, the 1-hour unbound plasma concentrations (Cu) were 0.051±0.024 (n=8), 0.19±0.11 (n=8), 0.58±0.35 (n=8), and 2.2±0.40 (n=8) μM, respectively. These values covered the in vitro rat TRPA1 45Ca2+ IC50 by 0.72, 2.7, 8.2, and 30.3 times, respectively. This target coverage model showed good exposure-response connections. The unbound in vivo IC90 is 1.7 μM, while the unbound in vivo IC50 is 0.35 μM, which is extremely comparable with the in vitro rat TRPA1 45Ca2+ IC50. Remarkably, AM-0902's binding concentration to TRPA1 at a dose of 30 mg/kg was greater than the in vivo IC90, indicating its potential utility in investigating acute pain models in vivo [1].
In an AITC-induced flinching model in rats, oral administration of AM-0902 (Compound 27) produced a dose-dependent reduction in nocifensive behavior. Significant reduction in flinching was observed at doses of 10 and 30 mg/kg. The unbound in vivo IC50 for target coverage was determined to be 0.35 µM, and the unbound in vivo IC90 was 1.7 µM. [1] |
| Enzyme Assay |
CYP Inhibition Assay: The inhibitory activity of AM-0902 (Compound 27) against cytochrome P450 enzymes was assessed. It showed no significant inhibition of CYP3A4 or CYP2D6, with estimated IC50 values greater than 27 µM for both isoforms. [1]
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| Cell Assay |
TRPA1 Calcium Flux (FLIPR) Assay: CHO cell lines stably expressing rat or human TRPA1 under a tetracycline-inducible promoter were used. Cells were seeded in 384-well plates and loaded with Fluo-4 NW calcium-sensitive dye. Test compound was added first to measure any agonist activity. After a 2-minute incubation, an EC90 concentration of the agonist AITC (3 µM for hTRPA1, 35 µM for rTRPA1) was added. Antagonist activity was measured as the inhibition of the subsequent calcium flux. IC50 values were determined by fitting data to a four-parameter equation.
⁴⁵Ca²⁺ Flux Assay: This assay directly measures the influx of radioactive calcium upon channel activation. Cells were pre-incubated with AM-0902 (Compound 27) for 10 minutes at room temperature. An agonist (AITC, methylglyoxal, or hypotonic buffer) along with ⁴⁵Ca²⁺ was then added for a 3-minute incubation. Cells were washed, and the retained radioactivity was measured. The reduction in agonist-induced ⁴⁵Ca²⁺ uptake was used to calculate IC50 values. Selectivity Assays: The activity of AM-0902 (Compound 27) against other TRP channels (hTRPV1, hTRPV4, rTRPV3, rTRPM8) was evaluated using similar calcium flux assays according to published procedures, with no activity observed up to 10 µM. [1] |
| Animal Protocol |
AITC-Induced Flinching Model in Rats: Rats were orally dosed with either vehicle (2% HPMC / 1% Tween-80) or AM-0902 (Compound 27) at 1, 3, 10, or 30 mg/kg. One hour post-dose, 0.1% AITC was injected into the left ventral hind paw. Nocifensive flinching behavior was then observed and recorded for the first minute post-injection. Plasma samples were collected to determine unbound drug concentrations (Cu) and establish an exposure-response relationship.
In Vivo Pharmacokinetic Studies: For intravenous (iv) PK studies, rats received a 0.5 mg/kg dose of AM-0902 (Compound 27) formulated in 100% DMSO. For oral (PO) PK studies, rats received a 30 mg/kg dose formulated in 1% Tween 80 / 2% HPMC / 97% water with methanesulfonic acid to adjust to pH 2.2. Blood samples were collected over time to determine plasma concentrations and calculate PK parameters. [1] AITC-Induced Flinching Model in Rats: Rats were orally dosed with either vehicle (2% HPMC / 1% Tween-80) or AM-0902 (Compound 27) at 1, 3, 10, or 30 mg/kg. One hour post-dose, 0.1% AITC was injected into the left ventral hind paw. Nocifensive flinching behavior was then observed and recorded for the first minute post-injection. Plasma samples were collected to determine unbound drug concentrations (Cu) and establish an exposure-response relationship. In Vivo Pharmacokinetic Studies: For intravenous (iv) PK studies, rats received a 0.5 mg/kg dose of AM-0902 (Compound 27) formulated in 100% DMSO. For oral (PO) PK studies, rats received a 30 mg/kg dose formulated in 1% Tween 80 / 2% HPMC / 97% water with methanesulfonic acid to adjust to pH 2.2. Blood samples were collected over time to determine plasma concentrations and calculate PK parameters. [1] |
| ADME/Pharmacokinetics |
AM-0902 (Compound 27) demonstrated favorable pharmacokinetic properties in rats.
Protein Binding: Rat plasma protein binding (PPB) fraction unbound (Fu) was 0.28. IV PK (0.5 mg/kg): Clearance (CL) was 2.59 L/h/kg, volume of distribution at steady state (Vss) was 1.7 L/kg, and half-life (T1/2) was 0.6 hours. Oral PK (30 mg/kg): Maximum total concentration (Cmax) was 7.5 µM (2.2 µM unbound), time to Cmax (Tmax) was 0.8 hours, oral half-life (T1/2) was 2.8 hours, and oral bioavailability (%F) was 60%. Target Coverage: At a 30 mg/kg oral dose, the unbound Cmax (2.2 µM) provided a 31-fold coverage over its in vitro rat TRPA1 ⁴⁵Ca²⁺ IC50 (0.071 µM). Permeability and Transport: AM-0902 (Compound 27) is highly permeable with an average apparent permeability (Papp) of 44.5 µm/s in MDCK cells. It is an unlikely substrate for P-glycoprotein (P-gp), with an efflux ratio of 1.3 in P-gp overexpressing MDCK cells. Solubility: It demonstrated good solubility in PBS at pH 7.4 (226 µM) and in simulated intestinal fluid (SIF, 248 µM). [1] |
| Toxicity/Toxicokinetics |
In a CEREP panel of 40 targets tested at a 10 µM concentration, AM-0902 (Compound 27) exhibited little to no inhibition (greater than 77% of control activity against all targets), suggesting a low risk for off-target toxicities.
It showed no significant inhibition of CYP3A4 or CYP2D6 (IC50 > 27 µM for both), indicating a low potential for drug-drug interactions via these major metabolic pathways. At a concentration of 10 µM, it caused only a 10% block of Naᵥ1.7 channels in mouse DRG neurons, suggesting that any in vivo efficacy in pain models is unlikely due to Naᵥ1.7 inhibition. [1] |
| References | |
| Additional Infomation |
AM-0902 (Compound 27) is a potent and selective TRPA1 antagonist identified through optimization of a high-throughput screening hit. It was developed as a tool compound to validate the role of TRPA1 in in vivo pain models. Its key features include high potency against both rat and human TRPA1, excellent selectivity over other TRP channels and a broad panel of off-targets, and favorable oral pharmacokinetics that allow for significant target coverage ( >30-fold over the in vitro IC50) in vivo following a 30 mg/kg oral dose in rats. This robust target coverage enabled the demonstration of dose-dependent efficacy in an AITC-induced flinching model in rats, confirming its utility for in vivo pharmacology studies. It is noted for its potential superiority over previously reported tool compounds. [1]
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| Molecular Formula |
C17H15CLN6O2
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|---|---|
| Molecular Weight |
370.793001413345
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| Exact Mass |
370.094
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| CAS # |
1883711-97-4
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| PubChem CID |
73297271
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| Appearance |
White to off-white solid powder
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
541
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=CC(=CC=1)CCC1=NOC(CN2C=NC3=C(C2=O)N(C)C=N3)=N1
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| InChi Key |
AWJBWNUUODWOKQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H15ClN6O2/c1-23-9-19-16-15(23)17(25)24(10-20-16)8-14-21-13(22-26-14)7-4-11-2-5-12(18)6-3-11/h2-3,5-6,9-10H,4,7-8H2,1H3
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| Chemical Name |
1-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)-7-methyl-1,7-dihydro-6H-purin-6-one
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| Synonyms |
AM-0902 AM 0902 AM0902.
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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 : ~150 mg/mL (~404.54 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.74 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 (6.74 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 25.0 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: ≥ 2.5 mg/mL (6.74 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 | 2.6969 mL | 13.4847 mL | 26.9694 mL | |
| 5 mM | 0.5394 mL | 2.6969 mL | 5.3939 mL | |
| 10 mM | 0.2697 mL | 1.3485 mL | 2.6969 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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