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| Targets |
Zaloglanstat specifically targets microsomal prostaglandin E synthase-1 (mPGES-1), an inducible enzyme that converts PGH2 to PGE2. mPGES-1 is upregulated at sites of inflammation and is a key enzyme in the production of pro-inflammatory PGE2. Zaloglanstat is a selective and orally active mPGES-1 inhibitor with an IC50 of 5 nM for human mPGES-1. It has no significant inhibitory effect on COX-1/2 (IC50 >10 microM), providing a mechanism for inhibiting PGE2 production without blocking the formation of other prostaglandins (e.g., PGI2, TXA2).
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| ln Vitro |
In vitro, Zaloglanstat (ISC-27864) is a selective inhibitor of mPGES-1 with an IC50 of 5 nM for human mPGES-1. It has no significant inhibitory effect on COX-1/2 (IC50 >10 microM). Zaloglanstat inhibits IL-1beta-induced PGE2 release in A549 cells and human synovial fibroblasts. In pig and dog whole blood, Zaloglanstat inhibits PGE2 release with IC50s of 161 nM and 154 nM, respectively. By selectively targeting mPGES-1, Zaloglanstat offers a promising therapeutic strategy to reduce inflammation while sparing the production of other prostaglandins that are important for gastric mucosal protection and renal function.
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| ln Vivo |
In vivo, Zaloglanstat exhibits significant analgesic effects in preclinical models of osteoarthritis and inflammatory arthritis. It is an orally active mPGES-1 inhibitor that demonstrates significant analgesic efficacy in preclinical models for osteoarthritis and inflammatory arthritis. Zaloglanstat may be utilized in research on asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain, and neurodegenerative diseases. It has also been studied for its potential to reduce PGE2-mediated pain and inflammation without the gastrointestinal and renal side effects associated with traditional NSAIDs.
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| Enzyme Assay |
The specific in vitro protocol for mPGES-1 inhibition uses a microsomal assay. Human recombinant mPGES-1 (10 ug) is incubated in assay buffer (100 mM sodium phosphate, pH 7.0, 2.5 mM GSH, 1.25 mM glutathione disulfide, 0.01% Tween-20) with varying concentrations of Zaloglanstat (0.01-1000 nM) for 10 minutes at room temperature. The substrate PGH2 (15 uM) is added, and the reaction is allowed to proceed for 1 minute at 4degC (to minimize non-enzymatic degradation). The reaction is stopped by the addition of FeCl2 (10 uL of 1 M). The amount of PGE2 produced is quantified by a PGE2-specific ELISA kit. The IC50 is calculated from the concentration-response curve (IC50 = 5 nM for human mPGES-1). COX-1/2 inhibition is assessed in parallel using ovine COX-1 and human recombinant COX-2 assays to confirm selectivity.
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| Cell Assay |
For in vitro cellular assays, human A549 lung epithelial cells or human synovial fibroblasts are seeded in 24-well plates and cultured in DMEM with 10% FBS. Cells are pre-incubated with Zaloglanstat (0.1-1000 nM) for 1 hour, then stimulated with IL-1beta (10 ng/mL) for 24 hours to induce mPGES-1 expression. Cell culture supernatants are collected, and PGE2 levels are measured by ELISA. Cell viability is assessed using the MTT assay. Zaloglanstat is expected to inhibit IL-1beta-induced PGE2 release in a concentration-dependent manner. For whole blood assays, pig or dog whole blood is collected, diluted 1:5 in RPMI 1640, and incubated with LPS (1 ug/mL) and Zaloglanstat (1-1000 nM) for 24 hours. Plasma is collected by centrifugation, and PGE2 levels are measured by ELISA (IC50s: pig = 161 nM, dog = 154 nM).
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| Animal Protocol |
An in vivo protocol for Zaloglanstat uses a rat model of carrageenan-induced paw edema (acute inflammation) or a monoiodoacetate (MIA)-induced osteoarthritis model. For the OA model, male Sprague-Dawley rats (150-200 g) receive a single intra-articular injection of MIA (3 mg in 50 uL saline) into the right knee joint. Zaloglanstat is administered orally by gavage at doses of 1, 3, 10, and 30 mg/kg (formulated in 0.5% methylcellulose) once daily starting on day 1 and continuing for 14-21 days. Paw withdrawal threshold (mechanical allodynia) is measured using von Frey filaments. Knee joint swelling is measured with a caliper. At study termination, knee joints are collected for histopathological assessment (H&E, safranin-O staining) and immunohistochemistry for PGE2 and IL-1beta. Serum and synovial fluid PGE2 levels are measured by ELISA.
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| ADME/Pharmacokinetics |
Zaloglanstat is an orally active mPGES-1 inhibitor. It has been evaluated in preclinical pharmacokinetic studies. The compound is orally bioavailable and has a favorable PK profile. Zaloglanstat inhibits PGE2 release in pig and dog whole blood with IC50s of 161 nM and 154 nM, respectively. Standard PK studies in rats would involve IV (1 mg/kg) and PO (5 mg/kg) administration to determine T1/2, Cmax, AUC, and oral bioavailability. Metabolism is likely mediated by hepatic CYP450 enzymes. Zaloglanstat has a molecular weight of 452.12 and a topological polar surface area of 79.26, indicating good cell membrane permeability.
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| Toxicity/Toxicokinetics |
Specific toxicology data for Zaloglanstat is not available. As a selective mPGES-1 inhibitor, the compound is designed to avoid the gastrointestinal and renal toxicities associated with non-selective NSAIDs and COX-2 inhibitors. Since mPGES-1 inhibition blocks PGE2 production while preserving PGI2 and TXA2 synthesis, the cardiovascular risk (thrombosis) associated with selective COX-2 inhibitors is theoretically reduced. Standard safety assessment would include in vitro hERG inhibition testing, CYP450 inhibition screening, and 28-day repeat-dose oral toxicity studies in rats and dogs to evaluate target organ toxicity and to determine the NOAEL.
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| References | |
| Additional Infomation |
Zaloglanstat is a small molecule drug. The International Nonproprietary Name (INN) stem "-glanstat" in its name indicates that zaloglanstat is a prostaglandin synthase inhibitor. The monoisotopic molecular weight of zaloglanstat is 452.12 Da.
Zaloglanstat (ISC-27864, GRC-27864) is an investigational drug and has not received regulatory approval for clinical use. It is a selective, orally active microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor (IC50 = 5 nM for human mPGES-1). Zaloglanstat blocks the conversion of arachidonic acid metabolite PGH2 to PGE2, thereby inhibiting inflammation-related PGE2 overproduction and reducing inflammatory responses and pain. It demonstrates significant analgesic efficacy in preclinical models of osteoarthritis and inflammatory arthritis. Zaloglanstat may be utilized in research on asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain, and neurodegenerative diseases. |
| Molecular Formula |
C21H20CLF3N4O2
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|---|---|
| Molecular Weight |
452.8573
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| Exact Mass |
452.122
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| CAS # |
1513852-12-4
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| PubChem CID |
136246033
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| Appearance |
White to off-white solid powder
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
714
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C([H])C(=C([H])C=1C1=NN(C(N1[H])=O)C1C([H])=C([H])C(C(F)(F)F)=C([H])C=1[H])C([H])([H])N([H])C(C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])=O
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| InChi Key |
DOVBVLUPCQSAGE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H20ClF3N4O2/c1-20(2,3)18(30)26-11-12-4-9-16(22)15(10-12)17-27-19(31)29(28-17)14-7-5-13(6-8-14)21(23,24)25/h4-10H,11H2,1-3H3,(H,26,30)(H,27,28,31)
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| Chemical Name |
N-[[4-chloro-3-[5-oxo-1-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl]phenyl]methyl]-2,2-dimethylpropanamide
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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: 250 mg/mL (552.05 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.59 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 | 2.2082 mL | 11.0409 mL | 22.0819 mL | |
| 5 mM | 0.4416 mL | 2.2082 mL | 4.4164 mL | |
| 10 mM | 0.2208 mL | 1.1041 mL | 2.2082 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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