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| Targets |
UPF-648 targets kynurenine 3-monooxygenase (KMO), a key enzyme in the kynurenine pathway of tryptophan degradation. KMO is responsible for the hydroxylation of L-kynurenine to 3-hydroxykynurenine. By potently inhibiting this enzyme, UPF-648 blocks the downstream production of neurotoxic metabolites such as quinolinic acid (QUIN). It demonstrates high selectivity for KMO, showing no inhibitory activity against kynurenine aminotransferase (KAT), which is responsible for the production of the neuroprotective metabolite kynurenic acid (KYNA).
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| ln Vitro |
At 1 and 0.1 mM, BFF 122 virtually entirely blocked KAT activity. At 0.01 mM, the impact was still considerable (inhibition of 70% ± 1%). BFF 122 had no discernible effect on KMO activity at the same three concentrations. Conversely, UPF 648 was generally ineffective in suppressing KAT activity, whereas it totally blocked KMO at 0.1 and 0.01 mM and remained highly active at 0.001 mM (81 ± 10% inhibition) [1]. UPF 648 forms a strong bond with the FAD cofactor, which causes the local active site structure to be upset and hinders the substrate L-kynurenine from binding efficiently. The yeast KMO-UPF 648 structure was validated as a template for structure-based drug design when functional assays and targeted mutagenesis revealed that the active site structure and UPF 648 binding are almost identical in human KMO [3].
UPF-648 demonstrates potent in vitro inhibitory activity against KMO. At a concentration of 1 µM, it achieves approximately 81% inhibition of KMO activity. It remains highly active even at 0.001 mM (1 µM), showing 81 ± 10% inhibition. In contrast, it is generally ineffective at suppressing KAT activity. The compound is believed to form a strong bond with the FAD cofactor of KMO, disrupting the active site structure and hindering substrate binding. |
| ln Vivo |
To investigate the impact of KMO inhibition on the de novo synthesis of KP metabolites in the damaged striatum, individual rats were employed in the same experimental design. The rats received bilateral injections of 3H-kynurenine and 0.1 mM UPF 648 in PBS. In damaged striatum, 0.1 mM UPF 648 considerably boosted de novo creation of KYNA [1] but significantly decreased de novo synthesis of 3-HK and QUIN (by 77% and 66%, respectively) and modestly (by 27%). Similar mass changes (i.e., significant increases in kynurenine and KYNA and decreases in 3-HK and QUIN) were observed in the brain and liver of pregnant rats and mice administered UPF 648 (50 mg/kg, i.p.) on the final day of gestation. When exposed to neonatal hypoxia right away, rat pups whose moms had received UPF 648 treatment had even greater elevation of brain KYNA levels [2]. With an IC50 of 20 nM, UPF 648 shields mice lacking kynurenine aminotransferase (KAT II) against intrastriatal QUIN injection. Additionally, KP metabolism is changed by UPF 648 therapy to promote the synthesis of neuroprotective KYNA [3].
In vivo studies have confirmed the activity of UPF-648 in modulating the kynurenine pathway. In rats with striatal lesions, administration of 0.1 mM UPF-648 significantly boosted the de novo creation of neuroprotective KYNA while decreasing the synthesis of neurotoxic 3-HK and QUIN by 77% and 66%, respectively. In pregnant rats and mice given 50 mg/kg UPF-648 (i.p.), similar changes were observed in the brain and liver. With an IC50 of 20 nM, UPF-648 also provides protection against intrastriatal QUIN injections in KAT II deficient mice. |
| Enzyme Assay |
Specific cell-free enzyme/receptor binding assay protocols for UPF-648 involve measuring its inhibitory activity against KMO. These assays typically use purified KMO enzyme and its substrate, L-kynurenine. The compound's inhibitory potency is determined by measuring the decrease in the formation of the product, 3-hydroxykynurenine, often using high-performance liquid chromatography (HPLC). Selectivity is confirmed by testing the compound against related enzymes like kynurenine aminotransferase (KAT) to ensure no cross-reactivity.
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| Cell Assay |
In vitro cell-based assays for UPF-648 are likely conducted using cell lines that express KMO, such as macrophages or microglia. Cells are treated with the compound, and its effect on the kynurenine pathway is assessed by measuring the levels of key metabolites (e.g., kynurenine, 3-HK, KYNA) in the cell culture supernatant using mass spectrometry or HPLC. The compound's ability to shift the balance from neurotoxic to neuroprotective metabolites is a key endpoint in these studies.
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| Animal Protocol |
In vivo animal studies for UPF-648 have been performed in rodent models. For example, rats received bilateral injections of 3H-kynurenine and 0.1 mM UPF-648 directly into the striatum. In other studies, pregnant rats and mice were administered UPF-648 at a dose of 50 mg/kg via intraperitoneal (i.p.) injection. Following treatment, brain and liver tissues were analyzed to measure changes in the concentrations of kynurenine pathway metabolites.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic properties of UPF-648 are not extensively reported in the provided literature. The compound has a molecular formula of C11H8Cl2O3 and a molecular weight of 259.09 g/mol. It is typically stored as a powder at -20°C and is soluble in DMSO at a concentration of 10 mM. Its in vivo activity has been demonstrated following intraperitoneal (i.p.) administration.
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| Toxicity/Toxicokinetics |
Specific toxicological data for UPF-648 are not detailed in the available literature. The compound is classified for research use only and is not intended for human therapeutic applications. As a potent inhibitor of KMO, its primary effects are related to its pharmacological activity on the kynurenine pathway, and formal toxicological profiles are not reported.
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| References |
[1]. Amori L, et al. On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo. J Neurochem. 2009 Apr;109(2):316-25.
[2]. Ceresoli-Borroni G, et al. Perinatal kynurenine 3-hydroxylase inhibition in rodents: pathophysiological implications. J Neurosci Res. 2007 Mar;85(4):845-54. [3]. Amaral M, et al. Structural basis of kynurenine 3-monooxygenase inhibition. Nature. 2013 Apr 18;496(7445):382-5. |
| Additional Infomation |
UPF-648 (CAS 213400-34-1) is a potent and selective kynurenine 3-monooxygenase (KMO) inhibitor used as a research tool to study the kynurenine pathway. It demonstrates high activity at 1 µM with 81% inhibition and has shown efficacy in shifting the balance of KP metabolites towards neuroprotective KYNA in vivo. No clinical trial or approved indication data are available for this compound.
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| Molecular Formula |
C11H8O3CL2
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| Molecular Weight |
259.08542
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| Exact Mass |
257.985
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| CAS # |
213400-34-1
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| Related CAS # |
UPF-648 sodium salt;1465017-87-1
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| PubChem CID |
9859947
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| Appearance |
White to off-white solid powder
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| LogP |
2.896
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
16
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| Complexity |
318
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O=C([C@@H]1[C@@H](C(C2=CC=C(Cl)C(Cl)=C2)=O)C1)O
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| InChi Key |
ZBRKMOHDGFGXLN-BQBZGAKWSA-N
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| InChi Code |
InChI=1S/C11H8Cl2O3/c12-8-2-1-5(3-9(8)13)10(14)6-4-7(6)11(15)16/h1-3,6-7H,4H2,(H,15,16)/t6-,7-/m0/s1
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| Chemical Name |
(1S,2S)-2-(3,4-dichlorobenzoyl)cyclopropane-1-carboxylic acid
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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) |
Ethanol :≥ 50 mg/mL (~192.98 mM)
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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 | 3.8597 mL | 19.2983 mL | 38.5966 mL | |
| 5 mM | 0.7719 mL | 3.8597 mL | 7.7193 mL | |
| 10 mM | 0.3860 mL | 1.9298 mL | 3.8597 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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