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| 25mg |
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| Targets |
LYS 006 specifically targets leukotriene A4 hydrolase (LTA4H) —the key enzyme catalyzing the conversion of leukotriene A4 (LTA4) to leukotriene B4 (LTB4). The Ki value for human LTA4H is 0.8 nM, and the IC50 value is 1.2 nM[1]
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| ln Vitro |
The modulation of arginine 7-amino-4-methylcoumarin (AMC) manpower (Arg-AMC), catalyzed by LTA4H, is inhibited by LTA4H-IN-1 (15 min) with an IC50 of 2 nM [1]. In the human whole blood assay (hWB), LTA4H-IN-1 (30 min) suppresses LTB4 production with an IC50 of 167 nM [1].
LTA4H Enzyme Inhibition: LYS 006 potently inhibited recombinant human, mouse, and rat LTA4H activity in a dose-dependent manner. IC50 values were 1.2 nM (human), 1.5 nM (mouse), and 1.8 nM (rat), with >95% inhibition at concentrations ≥10 nM[1] - LTB4 Production Inhibition in Immune Cells: In human polymorphonuclear leukocytes (PMNs) stimulated with calcium ionophore (A23187) to induce LTA4 synthesis, LYS 006 (0.1-10 nM) reduced LTB4 production by 50-92%. In mouse bone marrow-derived macrophages (BMDMs), it inhibited LPS-induced LTB4 release with an IC50 of 2.3 nM[1] - Selectivity for LTA4H: No significant inhibition of other related enzymes (e.g., 5-lipoxygenase, cyclooxygenase-1/2, leukotriene C4 synthase) at concentrations up to 1 μM, confirming high target selectivity[1] - No Cytotoxicity: No adverse effects on cell viability in human PMNs, BMDMs, or HeLa cells at concentrations up to 10 μM, as assessed by MTT assay[1] |
| ln Vivo |
LTA4H-IN-1 (0.3 mg/kg; one pass) reduced LTB4 release in mice by -43% as compared to vehicle [1].
Anti-Inflammatory Activity in Mouse Carrageenan-Induced Paw Edema Model: Oral administration of LYS 006 (0.1-10 mg/kg) dose-dependently inhibited paw edema formation. At 1 mg/kg, edema was reduced by 45% at 3 hours post-carrageenan injection; at 10 mg/kg, inhibition reached 72%, with efficacy maintained for 6 hours[1] - Inhibition of LTB4 Levels in Inflammatory Tissues: In the paw edema model, LYS 006 (5 mg/kg, oral) reduced LTB4 concentrations in edematous paw tissue by 68% compared to vehicle controls 3 hours post-stimulation[1] - Efficacy in Mouse Zymosan-Induced Peritonitis Model: Intraperitoneal administration of LYS 006 (0.3-3 mg/kg) reduced neutrophil infiltration into the peritoneal cavity by 35-65%. Oral dosing at 3 mg/kg achieved similar neutrophil reduction (58%)[1] - Anti-Arthritic Activity in Collagen-Induced Arthritis (CIA) Mouse Model: Oral LYS 006 (1-5 mg/kg/day) starting from disease onset reduced clinical arthritis scores by 40-60% over 21 days. It also decreased joint inflammation, cartilage erosion, and bone destruction, as shown by histopathological analysis[1] |
| Enzyme Assay |
Recombinant LTA4H Activity Assay: Recombinant human LTA4H was incubated with assay buffer containing LTA4 (substrate) and serial dilutions of LYS 006 (0.01-100 nM) at 37°C for 15 minutes. The reaction was terminated by adding acidified ethanol, and LTB4 (product) was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Inhibition curves were generated to calculate Ki and IC50 values[1]
- LTA4H Selectivity Assay: The inhibitory effect of LYS 006 (0.01 nM-1 μM) on other lipid mediator-related enzymes (5-lipoxygenase, COX-1/2, LTC4 synthase) was evaluated using their respective specific substrates and detection methods. Enzyme activity was measured via spectrophotometry or LC-MS/MS, with no significant inhibition observed for non-target enzymes[1] |
| Cell Assay |
Human PMN LTB4 Production Inhibition Assay: Human PMNs were isolated and suspended in culture medium. LYS 006 (0.01-100 nM) was added 30 minutes before stimulation with A23187 (1 μM) to induce LTA4 synthesis. After 1 hour incubation at 37°C, the supernatant was collected, and LTB4 levels were quantified by LC-MS/MS to calculate inhibition efficiency[1]
- Mouse BMDM LTB4 Release Assay: Mouse BMDMs were differentiated and plated in 24-well plates. LYS 006 (0.1-10 nM) was pre-incubated with cells for 1 hour, followed by LPS (1 μg/mL) stimulation for 4 hours. Supernatants were harvested, and LTB4 concentrations were measured via enzyme-linked immunosorbent assay (ELISA)[1] - Cell Viability Assay: Human PMNs, mouse BMDMs, or HeLa cells were seeded in 96-well plates and treated with LYS 006 (0.1 nM-10 μM) for 24 hours. MTT reagent was added, and absorbance at 570 nm was measured to assess mitochondrial activity and cell viability[1] |
| Animal Protocol |
Carrageenan-Induced Paw Edema Model: Male ICR mice (20-25 g) were randomly divided into groups (n=8/group). LYS 006 was dissolved in 0.5% carboxymethylcellulose sodium (CMC) and administered orally by gavage at 0.1, 1, 5, or 10 mg/kg 1 hour before subplantar injection of carrageenan (1% in saline). Paw volume was measured at 0, 1, 3, 6, and 24 hours post-carrageenan injection using a plethysmometer. Edematous paw tissue was collected at 3 hours for LTB4 quantification[1]
- Zymosan-Induced Peritonitis Model: Male C57BL/6 mice (22-28 g) received LYS 006 via intraperitoneal injection (0.3, 1, 3 mg/kg) or oral gavage (3 mg/kg) 30 minutes before intraperitoneal injection of zymosan (500 μg/mouse). After 4 hours, mice were euthanized, and peritoneal exudates were collected to count neutrophil numbers[1] - Collagen-Induced Arthritis (CIA) Model: DBA/1 mice (6-8 weeks old) were immunized with bovine type II collagen emulsified in complete Freund's adjuvant on day 0 and 21. LYS 006 (1, 3, 5 mg/kg/day) was administered orally from day 21 (disease onset) to day 42. Clinical arthritis scores (0-4 per paw) were assessed every 3 days. On day 42, hind paws were collected for histopathological analysis[1] - Pharmacokinetic Study: Male Sprague-Dawley rats (200-250 g) received a single oral dose of LYS 006 (10 mg/kg) or intravenous dose (3 mg/kg). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dosing. Plasma drug concentrations were measured by LC-MS/MS, and PK parameters were calculated[1] |
| ADME/Pharmacokinetics |
Absorption: The oral bioavailability of rats after a single oral dose of 10 mg/kg is 78%. The peak plasma concentration (Cmax) of 1.8 μg/mL is reached 1.5 hours after oral administration[1]
- Distribution: It is widely distributed in tissues, with the highest concentrations in the liver, spleen, and inflamed tissues (e.g., edematous paws) 2 hours after administration. The volume of distribution (Vd) in rats is 1.2 L/kg[1] - Metabolism: It is minimally metabolized in the liver; the parent compound accounts for 85% of the circulating drug-related substances. Only one inactive metabolite (oxidized derivative) was identified, accounting for <10% of the dose[1] - Excretion: It is mainly excreted unchanged in feces (65%) and urine (25%), and is eliminated from the body within 72 hours. Renal clearance (Clr) was 0.3 mL/min/kg[1] - Half-life: The terminal elimination half-life (t1/2) in rats (oral) was 6.8 hours, and in mice (oral) it was 5.2 hours[1] |
| Toxicity/Toxicokinetics |
Acute toxicity: No death or serious toxicity was observed in mice and rats at single oral doses up to 200 mg/kg. Mild transient weight loss (<5%) was observed at doses ≥100 mg/kg, which returned to normal within 3 days [1]
- Subchronic toxicity: No significant changes were observed in hematological parameters (erythrocytes, white blood cells, platelets), liver function (ALT, AST) or kidney function (BUN, creatinine) after continuous oral administration of 1-50 mg/kg LYS 006 to rats for 4 weeks. No histopathological lesions were detected in major organs (liver, kidney, heart, lungs) [1] - Plasma protein binding rate: determined by ultrafiltration, the plasma protein binding rate was high (92-94%) in human, mouse and rat plasma [1] - Drug interactions: no significant inhibitory effect on cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) was observed in human liver microsomes at concentrations up to 10 μM [1] |
| References | |
| Additional Infomation |
Background: LYS 006 is a synthetic heteroarylbutyric acid derivative that has been developed as a selective LTA4H inhibitor[1].
- Mechanism of action: It exerts its anti-inflammatory effect by inhibiting LTA4H-mediated LTB4 synthesis. LTB4 is a potent pro-inflammatory lipid mediator that promotes neutrophil recruitment, activation, and tissue damage in inflammatory and autoimmune diseases[1]. - Therapeutic indications: Based on preclinical efficacy in relevant animal models, LYS 006 is considered for the treatment of inflammatory diseases including rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD), and asthma[1]. - Formulation advantages: LYS 006 has been developed as an oral formulation with good water solubility and high oral bioavailability, supporting once-daily dosing[1]. |
| Molecular Formula |
C16H14CLFN6O3
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|---|---|
| Molecular Weight |
392.772164821625
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| Exact Mass |
392.08
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| Elemental Analysis |
C, 48.93; H, 3.59; Cl, 9.03; F, 4.84; N, 21.40; O, 12.22
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| CAS # |
1799681-85-8
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| PubChem CID |
118166560
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| Appearance |
White to off-white solid powder
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| LogP |
-0.4
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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 |
7
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| Heavy Atom Count |
27
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| Complexity |
499
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1=CC(=CC=C1C2=NN(N=N2)C[C@H](CC(=O)O)N)OC3=C(C=C(C=N3)Cl)F
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| InChi Key |
ZEGMEJVULDALSH-NSHDSACASA-N
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| InChi Code |
InChI=1S/C16H14ClFN6O3/c17-10-5-13(18)16(20-7-10)27-12-3-1-9(2-4-12)15-21-23-24(22-15)8-11(19)6-14(25)26/h1-5,7,11H,6,8,19H2,(H,25,26)/t11-/m0/s1
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| Chemical Name |
(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid
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| Synonyms |
LYS-006 LYS 006 LYS006
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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 : ~100 mg/mL (~254.60 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.37 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 (6.37 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 (6.37 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 | 2.5460 mL | 12.7301 mL | 25.4602 mL | |
| 5 mM | 0.5092 mL | 2.5460 mL | 5.0920 mL | |
| 10 mM | 0.2546 mL | 1.2730 mL | 2.5460 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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