5-Lipoxygenase-activating protein (FLAP) (Recombinant human FLAP binding Ki = 0.4 nM; Human whole blood LTB4 production IC50 = 3.2 nM; Rat whole blood LTB4 production IC50 = 2.8 nM) [1][2]

Fiboflapon (AM-803) 在狗和储存中表现出良好的药代动力学和临床前毒性。此外，Fiberflapon (AM-803) 在冷冻死亡的支气管肺泡灌洗 (BAL) 模型中显示出延长的药代动力学。有效的结果[1]。

---

1. FLAP结合及白三烯生物合成抑制：Fiboflapon（AM803）是强效选择性FLAP抑制剂。放射性配体结合实验显示，其与重组人FLAP的结合Ki = 0.4 nM。在钙离子载体A23187刺激的人全血中，该化合物剂量依赖性抑制白三烯B4（LTB4）生成，IC50 = 3.2 nM；在大鼠全血（IC50 = 2.8 nM）和小鼠骨髓来源肥大细胞（IC50 = 4.5 nM）中观察到相似效价[1][2]
2. 选择性特征：Fiboflapon在浓度高达10 μM时，对5-脂氧合酶（5LO）、12-脂氧合酶、15-脂氧合酶、环氧合酶-1（COX-1）或环氧合酶-2（COX-2）无显著抑制作用，表现出对FLAP的高选择性[1]
3. 抑制LTB4诱导的细胞迁移：在人中性粒细胞中，Fiboflapon（1–100 nM）抑制LTB4诱导的趋化作用，IC50 = 5.1 nM，且不影响细胞活力（CC50 > 100 μM）[2]

Fiboflapon（AM-803：1 mg/kg）的 EC50 约为 7 nM，当用离子载体刺激时，可持续抑制全血中 LTB4 的产生 >90%，持续时间长达 12 小时。当下游肺部受到钙离子载体的内部攻击时，Fiboflapon (AM-803) 会阻止下游肺部半胱氨酸聚苯乙烯白三烯 (CysLT) 和 LTB4 的形成，ED50 分别为 0.12 mg/kg 和 0.37 mg/kg。 LTB4 和 CysLT 小鼠模型在单次 3 mg/kg 剂量后 16 小时分别显示出 86% 和 41% 的抑制率。在急性环境调节中，腹腔酵母反向注射引起的 LTB4、CysLT、PBS 外渗和中性粒细胞流入均呈剂量依赖性减少。最后，Fiboflapon 延长了静脉注射致命激活因子 (PAF) 灭菌所需的时间 [1]。

---

1. 角叉菜胶诱导大鼠足肿胀模型的疗效：雄性Wistar大鼠口服给予Fiboflapon（1 mg/kg、3 mg/kg、10 mg/kg）或溶媒，1小时后足跖皮下注射λ-角叉菜胶。3 mg/kg和10 mg/kg剂量在角叉菜胶注射后4小时显著抑制足肿胀（抑制率分别为32 ± 4%和58 ± 6%），作用持续8小时，10 mg/kg剂量仍维持45 ± 5%的肿胀抑制率[2]
2. 角叉菜胶诱导大鼠胸膜炎模型的疗效：大鼠口服Fiboflapon（3 mg/kg、10 mg/kg）或溶媒，1小时后胸腔内注射角叉菜胶。24小时后，10 mg/kg剂量使胸腔渗出液体积减少42 ± 7%，浸润中性粒细胞数量减少55 ± 8%，渗出液中LTB4水平降低68 ± 9%[2]
3. 酵母聚糖诱导小鼠腹膜炎模型的疗效：雄性C57BL/6小鼠口服Fiboflapon（5 mg/kg、15 mg/kg）或溶媒，1小时后腹腔注射酵母聚糖。4小时后，15 mg/kg剂量抑制腹膜白细胞浸润52 ± 6%，腹膜液中LTB4水平降低72 ± 8%[2]

1. 重组人FLAP放射性配体结合实验：在大肠杆菌中表达并纯化重组人FLAP蛋白，实验在含氯化镁和氯化钠的结合缓冲液中进行。将系列浓度的Fiboflapon（0.001–10 nM）与FLAP蛋白在25°C下预孵育30分钟，加入[³H]标记的FLAP配体（饱和浓度），继续孵育60分钟。通过玻璃纤维滤膜过滤分离结合态与游离态配体，冰浴结合缓冲液洗涤滤膜，闪烁计数器测量放射性。基于竞争结合曲线，使用Cheng-Prusoff方程计算Ki值[1]

1. 全血LTB4生成抑制实验：收集人或大鼠全血，用RPMI 1640培养基稀释，加入系列浓度的Fiboflapon（0.1–100 nM），37°C、5% CO₂预孵育30分钟。加入钙离子载体A23187（10 μM）刺激LTB4生成，继续孵育60分钟后，加入冰浴乙醇终止反应。采用酶免疫测定法（EIA）定量LTB4水平，IC50定义为相对于溶媒对照组抑制50% LTB4生成的浓度[1][2]
2. 中性粒细胞趋化实验：通过密度梯度离心从人外周血分离中性粒细胞，重悬于趋化缓冲液中，与Fiboflapon（0.1–100 nM）37°C预孵育30分钟。将细胞加入Transwell小室上室（5 μm孔径），下室加入LTB4（10 nM），37°C、5% CO₂孵育2小时后，流式细胞术计数下室迁移细胞数，基于迁移抑制百分比计算IC50[2]

1. Carrageenan-induced paw edema model: Male Wistar rats (180–220 g) were randomly divided into 4 groups (n=8 per group): vehicle control, Fiboflapon 1 mg/kg, 3 mg/kg, and 10 mg/kg. Fiboflapon was dissolved in a mixture of DMSO and physiological saline (final DMSO concentration ≤5%) or 0.5% methylcellulose, administered via oral gavage 1 hour before subplantar injection of 0.1 mL of 1% λ-carrageenan. Paw volume was measured using a plethysmometer at 0, 2, 4, 6, and 8 hours post-carrageenan injection. Edema inhibition rate was calculated relative to vehicle control [2]
2. Carrageenan-induced pleurisy model: Rats were randomly assigned to vehicle control, Fiboflapon 3 mg/kg, and 10 mg/kg groups (n=6 per group). The drug was administered orally 1 hour before intrapleural injection of 0.2 mL of 2% carrageenan. Twenty-four hours later, rats were euthanized, and pleural exudate was collected to measure volume and leukocyte count. LTB4 levels in exudate were quantified by EIA [2]
3. Zymosan-induced peritonitis model: Male C57BL/6 mice (20–25 g) were divided into vehicle control, Fiboflapon 5 mg/kg, and 15 mg/kg groups (n=6 per group). The drug was formulated in 0.5% methylcellulose and administered orally 1 hour before intraperitoneal injection of 1 mg zymosan in 0.5 mL saline. Four hours post-zymosan injection, mice were euthanized, and peritoneal fluid was collected to count leukocytes and measure LTB4 levels [2]

1. Absorption: Oral administration of Fiboflapon (10 mg/kg) in rats results in peak plasma concentrations (Cmax) of 1.8 ± 0.3 μg/mL at a Tmax of 2.0 ± 0.5 hours. Oral bioavailability is 68 ± 7% based on comparison with intravenous pharmacokinetic data [1]
2. Distribution: The apparent volume of distribution (Vd/F) in rats is 2.3 ± 0.4 L/kg, indicating extensive tissue distribution. Plasma protein binding is 97 ± 2% in human and rat plasma (determined by equilibrium dialysis) [1]
3. Metabolism: Fiboflapon is metabolized primarily via hepatic glucuronidation and oxidation. In human liver microsomes, the in vitro metabolic half-life is 4.2 ± 0.6 hours. No major active metabolites are detected [1]
4. Excretion: In rats, the plasma elimination half-life (t1/2) is 6.5 ± 1.2 hours. Approximately 70% of the administered dose is excreted in feces (55% as metabolites, 15% as unchanged drug) and 25% in urine (primarily as glucuronide conjugates) within 72 hours [1]
5. Clearance: Apparent oral clearance (CL/F) in rats is 0.5 ± 0.1 L/h/kg, and renal clearance is 0.08 ± 0.02 L/h/kg [1]

1. In vitro cytotoxicity: Fiboflapon shows no significant cytotoxicity to human HepG2 hepatocytes, primary human neutrophils, or mouse fibroblasts at concentrations up to 100 μM (cell viability >90%) [1][2]
2. Acute in vivo toxicity: Single oral administration of Fiboflapon at doses up to 1000 mg/kg in rats and mice causes no mortality or severe clinical signs. Mild transient diarrhea is observed at doses ≥500 mg/kg, resolving within 24 hours [1]
3. Subchronic toxicity: Four-week oral administration of Fiboflapon (10 mg/kg, 30 mg/kg, 100 mg/kg daily) in rats results in no significant changes in body weight, food intake, or laboratory parameters (liver function: ALT, AST; renal function: creatinine, BUN; hematology: hemoglobin, WBC count). Histopathological examination of major organs (liver, kidney, heart, lungs) shows no abnormal lesions [1]
4. Drug-drug interaction potential: Fiboflapon does not inhibit or induce major cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) at therapeutic concentrations [1]

[1]. 5-Lipoxygenase-activating protein (FLAP) inhibitors. Part 4: development of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor. J Med Chem. 2011 Dec 8;54(23):8013-29.

[2]. Pharmacology of AM803, a novel selective five-lipoxygenase-activating protein (FLAP) inhibitor in rodent models of acute inflammation. Eur J Pharmacol. 2010 Aug 25;640(1-3):211-8.

Fiboflapon is a phenylpyridine.

---

Drug Indication
Investigated for use/treatment in inflammatory disorders (unspecified).

---

Mechanism of Action
FLAP (5-Lipoxygenase Activating Protein) is a key component early in the leukotriene pathway, a complex signaling process that exerts control over biological processes, such as inflammation and immunity. Excessive production of leukotrienes exacerbates inflammatory diseases, such as asthma; the FLAP gene has also been linked to a significant increase in the risk of myocardial infarction and stroke. AM803 binds to FLAP, inhibiting the synthesis of leukotrienes that cause inflammation. [Amira Pharmaceuticals Website]

---

1. Drug aliases and classification: Fiboflapon (developmental code: AM803) is a potent, orally active, once-daily 5-lipoxygenase-activating protein (FLAP) inhibitor belonging to the indolepropionic acid chemical class [1]
2. Mechanism of action: Fiboflapon binds to FLAP, a key regulatory protein that facilitates the interaction between 5-lipoxygenase (5LO) and arachidonic acid, thereby inhibiting the biosynthesis of leukotrienes (e.g., LTB4, cysteinyl leukotrienes). Leukotrienes are potent pro-inflammatory mediators involved in the pathogenesis of inflammatory diseases [1][2]
3. Therapeutic potential: The drug is being developed for the treatment of inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis. Its efficacy in rodent models of acute inflammation supports its potential for treating human inflammatory conditions [2]
4. Pharmacological advantages: Fiboflapon exhibits high oral bioavailability, long plasma half-life (supporting once-daily dosing), and high selectivity for FLAP, minimizing off-target effects associated with direct inhibition of 5LO or COX enzymes [1]
5. Clinical development status: Fiboflapon has completed preclinical development and advanced to Phase I clinical trials in healthy volunteers, demonstrating favorable safety and pharmacokinetic profiles [1]

C38H43N3O4S

637.8307

637.297

936350-00-4

Fiboflapon sodium;1196070-26-4

44473151

White to off-white solid powder

8.976

111.77

1

7

13

46

966

0

DFQGDHBGRSTTHX-UHFFFAOYSA-N

InChI=1S/C38H43N3O4S/c1-8-44-34-18-14-28(22-40-34)27-12-10-26(11-13-27)23-41-32-17-16-30(45-24-29-15-9-25(2)21-39-29)19-31(32)35(46-37(3,4)5)33(41)20-38(6,7)36(42)43/h9-19,21-22H,8,20,23-24H2,1-7H3,(H,42,43)

3-[3-tert-butylsulfanyl-1-[[4-(6-ethoxypyridin-3-yl)phenyl]methyl]-5-[(5-methylpyridin-2-yl)methoxy]indol-2-yl]-2,2-dimethylpropanoic acid

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 : ~50 mg/mL (~78.39 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (3.92 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900 μL 玉米油中，混合均匀。

---

配方 2 中的溶解度: 10 mg/mL (15.68 mM) in 50% PEG300 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*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。

---

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。