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Purity: ≥98%
Fiboflapon (also known as AM-803 and GSK2190915) is a novel,orally bioavailable and potent FLAP (5-Lipoxygenase-activating protein) inhibitor with binding IC50 of 2.9 nM. Fiboflapon attenuated the early (0-2 h) and late (4-10 h) asthmatic responses to inhaled allergen compared with placebo. GSK2190915 shows potential as a treatment for patients with asthma. Efficacy was demonstrated for GSK2190915 30 mg compared with placebo in day-time symptom scores and day-time SABA use.
| Targets |
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] |
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| ln Vitro |
Fiboflapon (AM-803) showed good pharmacokinetics and preclinical toxicity in dogs and storage. Moreover, fibroflapon (AM-803) shows protracted pharmacokinetics in the bronchoalveolar lavage (BAL) model of cryodont death. Efficacious outcomes [1].
1. FLAP binding and inhibition of leukotriene biosynthesis: Fiboflapon (AM803) is a potent and selective FLAP inhibitor. It binds to recombinant human FLAP with a Ki of 0.4 nM, as measured by a radioligand binding assay. In human whole blood stimulated with calcium ionophore A23187, the compound dose-dependently inhibits leukotriene B4 (LTB4) production with an IC50 of 3.2 nM. Similar potency is observed in rat whole blood (IC50 = 2.8 nM) and mouse bone marrow-derived mast cells (IC50 = 4.5 nM) [1][2] 2. Selectivity profile: Fiboflapon shows no significant inhibition of 5-lipoxygenase (5LO), 12-lipoxygenase, 15-lipoxygenase, cyclooxygenase-1 (COX-1), or cyclooxygenase-2 (COX-2) at concentrations up to 10 μM, demonstrating high selectivity for FLAP [1] 3. Inhibition of LTB4-induced cell migration: In human neutrophils, Fiboflapon (1–100 nM) inhibits LTB4-induced chemotaxis with an IC50 of 5.1 nM, without affecting cell viability (CC50 > 100 μM) [2] |
| ln Vivo |
Fiboflapon (AM-803: 1 mg/kg) has an EC50 of roughly 7 nM and persistently suppresses the production of LTB4 in whole blood when stimulated with an ionophore by >90% for up to 12 hours. Fiboflapon (AM-803) stops the formation of cysteine polystyrene leukotriene (CysLT) and LTB4 in the downstream lungs when they are internally challenged with calcium ionophores, with an ED50 of 0.12 mg/kg and 0.37 mg/kg, respectively. The LTB4 and CysLT mice models showed 86% and 41% inhibition rates, respectively, 16 hours after a single 3 mg/kg dosage. LTB4, CysLT, PBS extravasation, and neutrophil influx caused by peritoneal yeast reverse injection were all dose-dependently decreased by fibroflapon in acute environmental conditioning. And last, Fiboflapon lengthens the time needed for intravenous fatal activating factor (PAF) to sterilize [1].
1. Efficacy in carrageenan-induced rat paw edema: Male Wistar rats were orally administered Fiboflapon (1 mg/kg, 3 mg/kg, 10 mg/kg) or vehicle 1 hour before subplantar injection of λ-carrageenan. The 3 mg/kg and 10 mg/kg doses significantly inhibited paw edema at 4 hours post-carrageenan injection (32 ± 4% and 58 ± 6% inhibition, respectively, vs. vehicle). The effect persisted for 8 hours, with the 10 mg/kg dose maintaining 45 ± 5% edema inhibition [2] 2. Inhibition of carrageenan-induced pleurisy in rats: Rats were orally treated with Fiboflapon (3 mg/kg, 10 mg/kg) 1 hour before intrapleural injection of carrageenan. The 10 mg/kg dose reduced pleural exudate volume by 42 ± 7% and decreased the number of infiltrating neutrophils by 55 ± 8% compared to vehicle. Additionally, LTB4 levels in pleural exudate were reduced by 68 ± 9% at the 10 mg/kg dose [2] 3. Efficacy in zymosan-induced mouse peritonitis: Mice were orally administered Fiboflapon (5 mg/kg, 15 mg/kg) 1 hour before intraperitoneal injection of zymosan. The 15 mg/kg dose inhibited peritoneal leukocyte infiltration by 52 ± 6% and reduced LTB4 levels in peritoneal fluid by 72 ± 8% [2] |
| Enzyme Assay |
1. Recombinant human FLAP radioligand binding assay: Recombinant human FLAP protein was expressed in E. coli and purified. The assay was performed in binding buffer containing magnesium chloride and sodium chloride. Serial concentrations of Fiboflapon (0.001–10 nM) were pre-incubated with FLAP protein for 30 minutes at 25°C, followed by addition of [³H]-labeled FLAP ligand (saturating concentration). The mixture was incubated for another 60 minutes at 25°C, then filtered through glass fiber filters to separate bound and free ligand. Filters were washed with ice-cold binding buffer, and radioactivity was measured using a scintillation counter. Ki values were calculated using the Cheng-Prusoff equation from competition binding curves [1]
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| Cell Assay |
1. Whole blood LTB4 production inhibition assay: Human or rat whole blood was collected and diluted with RPMI 1640 medium. Serial concentrations of Fiboflapon (0.1–100 nM) were added to the blood samples and pre-incubated for 30 minutes at 37°C with 5% CO₂. Calcium ionophore A23187 (10 μM) was added to stimulate LTB4 production, and the samples were incubated for another 60 minutes. The reaction was terminated by adding ice-cold ethanol, and LTB4 levels were quantified using an enzyme immunoassay (EIA). The IC50 was defined as the concentration inhibiting LTB4 production by 50% relative to vehicle control [1][2]
2. Neutrophil chemotaxis assay: Human neutrophils were isolated from peripheral blood by density gradient centrifugation. Isolated neutrophils were resuspended in chemotaxis buffer and pre-incubated with Fiboflapon (0.1–100 nM) for 30 minutes at 37°C. The cells were added to the upper chamber of Transwell inserts (5 μm pores), and LTB4 (10 nM) was added to the lower chamber. After incubation for 2 hours at 37°C with 5% CO₂, migrated cells in the lower chamber were counted using flow cytometry. The IC50 was calculated based on the percentage of migration inhibition [2] |
| Animal Protocol |
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] |
| ADME/Pharmacokinetics |
1. Absorption: After oral administration of Fiboflapon (10 mg/kg) to rats, the peak plasma concentration (Cmax) was 1.8 ± 0.3 μg/mL, and the time to peak concentration (Tmax) was 2.0 ± 0.5 hours. The oral bioavailability was 68 ± 7% compared with the intravenous pharmacokinetic data [1]. 2. Distribution: The apparent volume of distribution (Vd/F) in rats was 2.3 ± 0.4 L/kg, indicating its extensive tissue distribution. The plasma protein binding rate in human and rat plasma was 97 ± 2% (determined by equilibrium dialysis) [1]. 3. Metabolism: Fiboflapon is mainly metabolized by hepatic glucuronidation and oxidation. In human liver microsomes, the in vitro metabolic half-life was 4.2 ± 0.6 hours. No major active metabolites were detected [1]
4. Excretion: In rats, the plasma elimination half-life (t1/2) was 6.5 ± 1.2 hours. Approximately 70% of the administered dose was excreted in feces within 72 hours (55% as metabolites and 15% as the original drug), and 25% was excreted in urine (mainly as glucuronide conjugates) [1] 5. Clearance: The apparent oral clearance (CL/F) in rats was 0.5 ± 0.1 L/h/kg, and the renal clearance was 0.08 ± 0.02 L/h/kg [1] |
| Toxicity/Toxicokinetics |
1. In vitro cytotoxicity: At concentrations up to 100 μM, Fiboflapon showed no significant cytotoxicity to human HepG2 hepatocytes, primary human neutrophils, or mouse fibroblasts (cell viability >90%) [1][2]. 2. Acute in vivo toxicity: Single oral doses of Fiboflapon up to 1000 mg/kg in rats and mice did not cause death or severe clinical symptoms. Mild, transient diarrhea was observed at doses ≥500 mg/kg, which resolved within 24 hours [1]. 3. Subchronic toxicity: After four consecutive weeks of oral administration of Fiboflapon (10 mg/kg, 30 mg/kg, and 100 mg/kg daily), no significant changes were observed in body weight, food intake, or laboratory parameters (liver function: ALT, AST; kidney function: creatinine, BUN; hematology: hemoglobin, white blood cell count). Histopathological examination of major organs (liver, kidney, heart, lungs) showed no abnormal lesions [1]
4. Drug interaction risk: At therapeutic concentrations, Fiboflapon does not inhibit or induce major cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) [1] |
| References |
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| Additional Infomation |
Fiboflapon is a phenylpyridine compound. Drug Indications It has been investigated for the treatment of inflammatory diseases (not specified). Mechanism of Action FLAP (5-lipoxygenase activator protein) is a key early component of the leukotriene pathway, a complex signaling pathway that regulates biological processes such as inflammation and immunity. Excessive leukotriene production exacerbates inflammatory diseases such as asthma; the FLAP gene is also significantly associated with an increased risk of myocardial infarction and stroke. AM803 binds to FLAP, inhibiting the synthesis of inflammatory leukotrienes. [Amira Pharmaceuticals website]
1. Drug aliases and classification: Fiboflapon (development code: AM803) is a potent, orally effective, once-daily 5-lipoxygenase-activated protein (FLAP) inhibitor belonging to the indolepropionic acid class of compounds [1] 2. Mechanism of action: Fiboflapon binds to FLAP, a key regulatory protein that promotes the interaction between 5-lipoxygenase (5LO) and arachidonic acid, thereby inhibiting the biosynthesis of leukotrienes (e.g., LTB4, cysteyl leukotrienes). Leukotrienes are potent pro-inflammatory mediators involved in the pathogenesis of inflammatory diseases [1][2] 3. Therapeutic potential: This drug is being developed for the treatment of inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis. Its efficacy in acute inflammatory rodent models supports its potential for treating human inflammatory diseases [2] 4. Pharmacological advantages: Fiboflapon has high oral bioavailability, a long plasma half-life (supporting once-daily dosing), and high selectivity for FLAP, thereby minimizing off-target effects associated with direct inhibition of 5LO or COX enzymes [1] 5. Clinical development status: Fiboflapon has completed preclinical development and has entered a Phase I clinical trial in healthy volunteers, showing good safety and pharmacokinetic characteristics [1] |
| Molecular Formula |
C38H43N3O4S
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|---|---|
| Molecular Weight |
637.8307
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| Exact Mass |
637.297
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| CAS # |
936350-00-4
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| Related CAS # |
Fiboflapon sodium;1196070-26-4
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| PubChem CID |
44473151
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| Appearance |
White to off-white solid powder
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| LogP |
8.976
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
46
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| Complexity |
966
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
DFQGDHBGRSTTHX-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
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
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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 : ~50 mg/mL (~78.39 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.92 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 10 mg/mL (15.68 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5678 mL | 7.8391 mL | 15.6782 mL | |
| 5 mM | 0.3136 mL | 1.5678 mL | 3.1356 mL | |
| 10 mM | 0.1568 mL | 0.7839 mL | 1.5678 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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