LYS 006

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]

LTA4H 催化的精氨酸 7-氨基-4-甲基香豆素 (AMC) 人力 (Arg-AMC) 调节被 LTA4H-IN-1（15 分钟）抑制，IC50 为 2 nM [1]。在人全血测定 (hWB) 中，LTA4H-IN-1（30 分钟）抑制 LTB4 的产生，IC50 为 167 nM [1]。

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LTA4H酶抑制活性：LYS 006 以剂量依赖性方式强效抑制重组人、小鼠和大鼠LTA4H活性。IC50值分别为1.2 nM（人）、1.5 nM（小鼠）和1.8 nM（大鼠），浓度≥10 nM时抑制率>95%[1]
- 免疫细胞中LTB4生成抑制：在经钙离子载体（A23187）刺激以诱导LTA4合成的人多形核白细胞（PMNs）中，0.1-10 nM的LYS 006 可减少50%-92%的LTB4生成。在小鼠骨髓来源巨噬细胞（BMDMs）中，其抑制LPS诱导的LTB4释放的IC50为2.3 nM[1]
- LTA4H选择性：浓度高达1 μM时，对其他相关酶（如5-脂氧合酶、环氧合酶-1/2、白三烯C4合酶）无显著抑制作用，证实具有高靶点选择性[1]
- 无细胞毒性：MTT法检测显示，浓度高达10 μM时，对人PMNs、BMDMs或HeLa细胞的活力无不良影响[1]

与媒介物相比，LTA4H-IN-1（0.3 mg/kg；一次通过）使小鼠体内的 LTB4 释放量减少了 -43% [1]。

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小鼠角叉菜胶诱导足肿胀模型的抗炎活性：口服给予0.1-10 mg/kg的LYS 006，可剂量依赖性抑制足肿胀形成。1 mg/kg剂量下，角叉菜胶注射后3小时肿胀减轻45%；10 mg/kg剂量下抑制率达72%，药效维持6小时[1]
- 炎症组织中LTB4水平抑制：在足肿胀模型中，口服5 mg/kg LYS 006 后，刺激后3小时水肿足组织中的LTB4浓度较溶媒对照组降低68%[1]
- 小鼠酵母聚糖诱导腹膜炎模型的疗效：腹腔注射0.3-3 mg/kg LYS 006，可减少35%-65%的中性粒细胞向腹腔浸润；口服3 mg/kg可达到类似的中性粒细胞减少效果（58%）[1]
- 胶原诱导关节炎（CIA）小鼠模型的抗关节炎活性：从疾病发作时开始口服给予1-5 mg/kg/天的LYS 006，21天内可降低40%-60%的临床关节炎评分。组织病理学分析显示，其还可减轻关节炎症、软骨侵蚀和骨破坏[1]

重组LTA4H活性实验：将重组人LTA4H与含LTA4（底物）和系列稀释（0.01-100 nM）LYS 006 的反应缓冲液在37°C孵育15分钟，加入酸化乙醇终止反应，通过液相色谱-串联质谱（LC-MS/MS）定量产物LTB4，绘制抑制曲线并计算Ki和IC50值[1]
- LTA4H选择性实验：采用各酶的特异性底物和检测方法，评估LYS 006（0.01 nM-1 μM）对其他脂质介质相关酶（5-脂氧合酶、COX-1/2、LTC4合酶）的抑制作用，通过分光光度法或LC-MS/MS检测酶活性，对非靶点酶未观察到显著抑制[1]

人PMNs LTB4生成抑制实验：分离人PMNs并悬浮于培养基中，加入LYS 006（0.01-100 nM）预处理30分钟后，用A23187（1 μM）刺激诱导LTA4合成。37°C孵育1小时后收集上清液，通过LC-MS/MS定量LTB4水平，计算抑制效率[1]
- 小鼠BMDMs LTB4释放实验：将分化后的小鼠BMDMs接种到24孔板中，加入LYS 006（0.1-10 nM）预孵育1小时，随后用LPS（1 μg/mL）刺激4小时。收集上清液，通过酶联免疫吸附试验（ELISA）检测LTB4浓度[1]
- 细胞活力实验：将人PMNs、小鼠BMDMs或HeLa细胞接种到96孔板中，用LYS 006（0.1 nM-10 μM）处理24小时，加入MTT试剂，检测570 nm处吸光度以评估线粒体活性和细胞活力[1]

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]

Absorption: Oral bioavailability in rats was 78% after a single 10 mg/kg dose. Peak plasma concentration (Cmax) of 1.8 μg/mL was reached 1.5 hours post-oral dosing[1]
- Distribution: Widely distributed in tissues, with highest concentrations in the liver, spleen, and inflammatory tissues (e.g., edematous paws) at 2 hours post-dosing. Volume of distribution (Vd) was 1.2 L/kg in rats[1]
- Metabolism: Minimally metabolized in the liver; the parent compound accounted for 85% of circulating drug-related material. A single inactive metabolite (oxidative derivative) was identified, accounting for <10% of the dose[1]
- Excretion: Excreted primarily via feces (65%) and urine (25%) as unchanged drug within 72 hours. Renal clearance (Clr) was 0.3 mL/min/kg[1]
- Half-Life: Terminal elimination half-life (t1/2) was 6.8 hours in rats (oral) and 5.2 hours in mice (oral)[1]

Acute Toxicity: Single oral doses of up to 200 mg/kg in mice and rats did not cause mortality or severe toxicity. Mild transient weight loss (<5%) was observed at doses ≥100 mg/kg, resolving within 3 days[1]
- Subchronic Toxicity: Rats treated with 1-50 mg/kg/day oral LYS 006 for 4 weeks showed no significant changes in hematological parameters (RBC, WBC, platelets), liver function (ALT, AST), or kidney function (BUN, creatinine). No histopathological lesions were detected in major organs (liver, kidney, heart, lung)[1]
- Plasma Protein Binding: High plasma protein binding (92-94%) in human, mouse, and rat plasma, as determined by ultrafiltration[1]
- Drug-Drug Interactions: No significant inhibition of cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) at concentrations up to 10 μM in human liver microsomes[1]

[1]. Heteroaryl butanoic acid derivatives as leukotriene A4 hydrolase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of diseases. WO2015092740A1.

Background: LYS 006 is a synthetic heteroaryl butanoic acid derivative developed as a selective LTA4H inhibitor[1]
- Mechanism of Action: Exerts anti-inflammatory effects 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: Proposed for the treatment of inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD), and asthma, based on preclinical efficacy in relevant animal models[1]
- Formulation Advantages: Developed as an oral formulation with good aqueous solubility and high oral bioavailability, supporting once-daily dosing[1]

C16H14CLFN6O3

392.772164821625

392.08

C, 48.93; H, 3.59; Cl, 9.03; F, 4.84; N, 21.40; O, 12.22

1799681-85-8

118166560

White to off-white solid powder

-0.4

129

2

9

7

27

499

1

C1=CC(=CC=C1C2=NN(N=N2)C[C@H](CC(=O)O)N)OC3=C(C=C(C=N3)Cl)F

ZEGMEJVULDALSH-NSHDSACASA-N

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

(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid

LYS-006 LYS 006 LYS006

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~254.60 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.37 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.37 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.37 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。