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| Targets |
ABHD12 (alpha/beta-hydrolase domain-containing protein 12). DO-264 is a selective inhibitor of ABHD12, a lyso-PS lipase implicated in lipid signaling and neuroimmune regulation. It inhibits ABHD12-dependent hydrolysis of lysophosphatidylserine (lyso-PS).
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| ln Vitro |
The IC50 value for DO-264 is 11 nM (9.6 nM–13 nM). DO-264 inhibits ABHD12-dependent hemolytic PS hydrolysis Lipase activity in mouse meningeal lysate (IC50=2.8 nM, 2.4 nM-3.3 nM) and human THP-1 cells (IC50= 8.6 nM, 6.3 nM-12 nM), as well as the hemolytic PS hydrolytic activity of recombinant mouse and human ABHD12 in transfected HEK293T cell lysates (DO-264 IC50 values are roughly 30 and 90 nM for mouse and human ABHD12, respectively) [1].
DO-264 inhibits ABHD12 with an IC₅0 of 11 nM. It inhibits ABHD12-dependent lyso-PS lipase activity of membrane lysates from mouse brain with an IC₅0 of 2.8 nM. The compound is a potent, selective, reversible, and in vivo-active inhibitor. |
| ln Vivo |
There was a dose-dependent increase in hemolytic PS and 20:4 PS content in the brains of mice treated with DO-264, which was qualitatively similar to the changes found in ABHD12–/– mice. However, mice treated with DO-264 demonstrated minor decrease in hearing function 4 weeks following drug administration. Both ABHD12–/– and DO-264-treated mice demonstrated deterioration of immunopathology after infection with lymphocytic choriomeningitis virus (LCMV) clone 13, leading in severe inflammatory lung damage, increased chemokine production, In some cases it even leads to death[1].
In vivo, DO-264 is an in vivo-active inhibitor of ABHD12. By inhibiting ABHD12, the compound modulates lyso-PS levels and neuroimmune signaling. Efficacy would be assessed in models of neuroinflammation, immune regulation, and neurodegenerative diseases where ABHD12 plays a role. |
| Enzyme Assay |
ABHD12 enzymatic activity is measured using a lipase assay with a fluorogenic or radiolabeled substrate. Recombinant ABHD12 or membrane preparations containing ABHD12 are incubated with a lyso-PS substrate and serial dilutions of test compound. Product formation is quantified, and IC₅0 values are calculated from dose-response curves.
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| Cell Assay |
Cells (e.g., THP-1 macrophages, microglia) are treated with DO-264 at various concentrations. Lyso-PS hydrolysis is measured by LC-MS/MS. Inflammatory cytokine production is assessed by ELISA. Phagocytosis assays are performed to evaluate the functional effects of ABHD12 inhibition. Cell viability is assessed using MTT or CellTiter-Glo assays.
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| Animal Protocol |
Mouse models of neuroinflammation, immune regulation, or neurodegenerative diseases are administered DO-264 via appropriate routes. Lyso-PS levels in brain and peripheral tissues are quantified by LC-MS/MS. Inflammatory markers and immune cell populations are assessed. Efficacy is determined by disease outcome measures and biomarker modulation.
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| ADME/Pharmacokinetics |
DO-264 has a molecular weight of 558.40 g/mol and formula C23H20Cl2F3N₅O2S. Standard PK parameters (half-life, Cmax, AUC, clearance, volume of distribution) would be determined in rodent studies. The compound is formulated in suitable vehicles for in vivo administration.
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| Toxicity/Toxicokinetics |
Toxicology data for DO-264 are not publicly available. Standard preclinical safety assessment would include cytotoxicity screening, hERG testing, and repeat-dose toxicology studies in rodents. Given the role of ABHD12 in lipid signaling and neuroimmune regulation, potential on-target effects would be evaluated.
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| References | |
| Additional Infomation |
DO-264 is a research compound for studying ABHD12 biology, lipid signaling, and neuroimmune regulation. It is not clinically approved. The compound is a potent, selective, and in vivo-active ABHD12 inhibitor with an IC₅0 of 11 nM. It is useful for investigating the role of ABHD12 and lyso-PS in neuroinflammation, immune function, and neurodegenerative diseases.
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| Molecular Formula |
C23H20CL2F3N5O2S
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|---|---|
| Molecular Weight |
558.403411865234
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| Exact Mass |
557.066
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| CAS # |
2301866-59-9
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| PubChem CID |
134813646
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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 |
601.5±65.0 °C at 760 mmHg
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| Flash Point |
317.6±34.3 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.653
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| LogP |
5.44
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
36
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| Complexity |
720
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CN(CCC1NC(=S)NC2=CN=CC=C2)C3=NC=CC(=C3Cl)OC4=C(C=C(C=C4)OC(F)(F)F)Cl
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| InChi Key |
PIEQDBPBBQPLPL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H20Cl2F3N5O2S/c24-17-12-16(35-23(26,27)28)3-4-18(17)34-19-5-9-30-21(20(19)25)33-10-6-14(7-11-33)31-22(36)32-15-2-1-8-29-13-15/h1-5,8-9,12-14H,6-7,10-11H2,(H2,31,32,36)
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| Chemical Name |
1-[1-[3-chloro-4-[2-chloro-4-(trifluoromethoxy)phenoxy]pyridin-2-yl]piperidin-4-yl]-3-pyridin-3-ylthiourea
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 (~179.08 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.72 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 20.8 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: ≥ 2.08 mg/mL (3.72 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 20.8 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 | 1.7908 mL | 8.9542 mL | 17.9083 mL | |
| 5 mM | 0.3582 mL | 1.7908 mL | 3.5817 mL | |
| 10 mM | 0.1791 mL | 0.8954 mL | 1.7908 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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