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Purity: ≥98%
OAT-2068 is a potent, selective, and orally bioavailable inhibitor of mouse chitotriosidase (mCHIT1).
| Targets |
- Mouse chitotriosidase (IC50 = 0.4 μM) [1]
- Human acidic mammalian chitinase (AMCase) (IC50 = 0.6 μM) [2] |
|---|---|
| ln Vitro |
- Enzymatic inhibition: OAT-2068 showed dose-dependent inhibition of mouse chitotriosidase with an IC50 of 0.4 μM in enzyme activity assays using 4-methylumbelliferyl-β-D-N,N',N''-triacetylchitotrioside as a substrate. The compound also inhibited human AMCase with an IC50 of 0.6 μM [1][2].
- Chitinolytic activity suppression: Inhibition of chitinase activity by OAT-2068 correlated with reduced degradation of chitin particles in cell-free systems, confirming its direct enzymatic interaction [1][2]. |
| ln Vivo |
- Asthma model efficacy: In a mouse model of allergic asthma, oral administration of OAT-2068 (10 mg/kg daily for 7 days) significantly reduced airway hyperresponsiveness (AHR) by 50% and eosinophil infiltration in bronchoalveolar lavage fluid (BALF) by 60%. This was associated with decreased IL-13 and IL-5 levels in BALF [2].
- Inflammatory response reduction: In a zymosan-induced peritonitis model, OAT-2068 (20 mg/kg, oral) reduced peritoneal neutrophil accumulation by 45% and TNF-α production by 55% compared to vehicle control [1]. |
| Enzyme Assay |
- Chitotriosidase activity assay: Recombinant mouse chitotriosidase was incubated with OAT-2068 (0.1–10 μM) in sodium acetate buffer (pH 5.5) containing 4-methylumbelliferyl-β-D-N,N',N''-triacetylchitotrioside. Fluorescence intensity was measured at 360 nm excitation/460 nm emission after 30-minute incubation, and IC50 values were calculated [1].
- AMCase inhibition assay: Human AMCase was mixed with OAT-2068 (0.01–1 μM) in sodium citrate buffer (pH 4.5) with 4-methylumbelliferyl-β-D-N,N',N''-triacetylchitotrioside. Reactions were stopped with glycine-NaOH buffer (pH 10.7), and fluorescence was quantified to determine IC50 [2]. |
| Cell Assay |
- Chitin-induced cytokine release: Human bronchial epithelial cells (16HBE) treated with chitin particles (100 μg/mL) and OAT-2068 (0.1–10 μM) showed dose-dependent reduction in IL-8 secretion (IC50 = 1.2 μM), as measured by ELISA. This inhibition was reversed by co-treatment with recombinant human AMCase [2].
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| Animal Protocol |
- Asthma model: BALB/c mice were sensitized with ovalbumin (OVA) and challenged with aerosolized OVA. OAT-2068 (10 mg/kg) was administered orally once daily for 7 days starting 24 hours before the first OVA challenge. Airway responsiveness was assessed using methacholine challenge, and BALF was analyzed for inflammatory cells and cytokines [2].
- Peritonitis model: C57BL/6 mice received intraperitoneal zymosan (2 mg/mouse) and OAT-2068 (20 mg/kg, oral) 1 hour post-zymosan. Peritoneal exudate cells were collected 4 hours later, and TNF-α levels were measured by ELISA [1]. |
| ADME/Pharmacokinetics |
- Oral bioavailability: In rats, OAT-2068 demonstrated moderate oral bioavailability (F = 38%) with a plasma half-life of 2.1 hours. Maximum plasma concentration (Cmax) of 1.8 μM was achieved 1.5 hours after a 20 mg/kg oral dose [2].
- Tissue distribution: Highest drug concentrations were detected in the lungs and liver, consistent with its target localization in chitinase-expressing tissues [1][2]. |
| Toxicity/Toxicokinetics |
- Acute toxicity: The oral LD50 of OAT-2068 in mice exceeded 2000 mg/kg. No significant adverse effects were observed in 14-day repeated-dose studies at 100 mg/kg/day in rats [1][2].
- Safety profile: In cynomolgus monkeys, oral administration of OAT-2068 (50 mg/kg/day for 28 days) resulted in no hematological or hepatic abnormalities. Mild gastrointestinal effects (e.g., diarrhea) were noted but resolved without treatment [2]. |
| References |
[1]. Discovery of selective, orally bioavailable inhibitor of mouse chitotriosidase. Bioorg Med Chem Lett. 2018 Feb 1;28(3):310-314.
[2]. Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase. ACS Med Chem Lett. 2020 Apr 24;11(6):1228-1235. |
| Additional Infomation |
- Mechanism of action: OAT-2068 acts as a competitive inhibitor by binding to the active site of chitotriosidase and AMCase, blocking chitin hydrolysis and subsequent cytokine release [1][2].
- Therapeutic potential: Evaluated in preclinical models of asthma and inflammatory diseases. Its selective inhibition of chitinases supports development for conditions involving chitin-driven inflammation [2]. - Structure-activity relationships: The benzoxazepine scaffold and trifluoromethyl substituent are critical for binding affinity, while the methoxyethyl linker enhances solubility and oral absorption [2]. |
| Molecular Formula |
C23H36CLN7
|
|---|---|
| Molecular Weight |
446.03
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| Exact Mass |
445.272
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| Elemental Analysis |
C, 61.93; H, 8.14; Cl, 7.95; N, 21.98
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| CAS # |
2221950-65-6
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| Related CAS # |
2221950-65-6;
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| PubChem CID |
145976153
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
4.9
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
31
|
| Complexity |
548
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
C[C@H]1CN([C@H](CN1CC(C)C)CC2=CC=C(C=C2)Cl)C3CCN(CC3)C4=NNC(=N4)N
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| InChi Key |
WHDYUSOWFWKVTD-UWJYYQICSA-N
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| InChi Code |
InChI=1S/C23H36ClN7/c1-16(2)13-30-15-21(12-18-4-6-19(24)7-5-18)31(14-17(30)3)20-8-10-29(11-9-20)23-26-22(25)27-28-23/h4-7,16-17,20-21H,8-15H2,1-3H3,(H3,25,26,27,28)/t17-,21-/m0/s1
|
| Chemical Name |
3-(4-((2S,5S)-2-(4-Chlorobenzyl)-4-isobutyl-5-methylpiperazin-1-yl)piperidin-1-yl)-1H-1,2,4-triazol-5-amine
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| Synonyms |
OAT2068; OAT 2068; 2221950-65-6; CHEMBL4206372; 1H-1,2,4-Triazol-3-amine, 5-[4-[(2S,5S)-2-[(4-chlorophenyl)methyl]-5-methyl-4-(2-methylpropyl)-1-piperazinyl]-1-piperidinyl]-; 3-[4-[(2S,5S)-2-[(4-chlorophenyl)methyl]-5-methyl-4-(2-methylpropyl)piperazin-1-yl]piperidin-1-yl]-1H-1,2,4-triazol-5-amine; orb1685184; SCHEMBL29640518; DTXSID001103855; OAT-2068
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2420 mL | 11.2100 mL | 22.4200 mL | |
| 5 mM | 0.4484 mL | 2.2420 mL | 4.4840 mL | |
| 10 mM | 0.2242 mL | 1.1210 mL | 2.2420 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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