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Purity: ≥98%
AMG-009 is a novel, potent, orally bioactive, small molecule antagonist of prostaglandin D2, with IC50 of 3 nM and 12 nM for CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) and DP (D prostanoid) receptors, respectively. For the treatment of allergic rhinitis and asthma, AMG 009 was undergoing preclinical development in the US.
| Targets |
DP ( IC50 = 3 nM )
AMG-009 targets Chemoattractant Receptor-homologous molecule expressed on Th2 cells (CRTH2/DP2) and Prostaglandin D2 receptor (DP/DP1) (CRTH2: Ki = 1.2 nM, IC50 = 3.5 nM for PGD2-induced calcium mobilization [1] ; DP: Ki = 4.8 nM, IC50 = 12 nM for PGD2-induced cAMP inhibition [1] ; no significant binding to other prostaglandin receptors (EP1-4, FP, TP) with Ki > 1000 nM [1] ) |
|---|---|
| ln Vitro |
AMG-009 prevents PGD2-induced down-modulation of CRTH2 on CD16 negative granulocytes (eosinophils) in human whole blood with a Ki of 1 nM. Additionally, AMG 009 has a Ki of 148 nM against PGD2-induced cAMP response mediated by DP in platelets in 80% of human whole blood. Guinea pig DP receptor-expressing cells (Ki=131 nM) in an assay for PGD2-induced cAMP response are inhibited by AMG 009 (IC50=3 nM)[1].
1. AMG-009 acted as a potent dual antagonist of CRTH2 and DP receptors, inhibiting PGD2-induced calcium mobilization in CRTH2-transfected HEK293 cells with an IC50 of 3.5 nM and blocking PGD2-mediated cAMP production inhibition in DP-transfected CHO cells with an IC50 of 12 nM [1] 2. In human eosinophils, AMG-009 (1-100 nM) dose-dependently inhibited PGD2-induced chemotaxis (IC50 = 5.2 nM) and shape change (IC50 = 4.1 nM), with complete inhibition observed at 100 nM [1] 3. AMG-009 showed time-dependent inhibition of CYP3A4 activity in human liver microsomes; preincubation of AMG-009 (1 μM) with CYP3A4 for 30 minutes resulted in a 75% reduction in enzyme activity, compared to 20% inhibition without preincubation [3] 4. In human Th2 lymphocytes, AMG-009 (10 nM) suppressed PGD2-induced release of IL-4 and IL-13 by 60% and 55%, respectively, demonstrating inhibition of Th2 cytokine production [1] |
| ln Vivo |
AMG 009 (3, 10 or 30 mg/kg, s.c.) in an acute guinea pig model causes a dose-dependent decrease in airway resistance triggered by PGD2 aerosol[1]. AMG 009, with a Kb of 82 nM, dramatically increases DP potency in a guinea pig model of PGD2-induced airway constriction[2].
1. In a mouse model of allergic airway inflammation (ovalbumin-sensitized/challenged), oral administration of AMG-009 (10, 30, 100 mg/kg once daily for 7 days) dose-dependently reduced eosinophil infiltration into the lungs (by 35%, 62%, and 85% respectively) and decreased BALF levels of IL-4, IL-5, and IL-13 (by 40-70%) [1] 2. In a guinea pig model of PGD2-induced bronchoconstriction, AMG-009 (3 mg/kg intravenously) inhibited airway resistance increase by 78%, while the 10 mg/kg oral dose achieved 65% inhibition [1] |
| Enzyme Assay |
1. CRTH2/DP receptor binding assay: Membrane preparations from CRTH2-transfected HEK293 cells or DP-transfected CHO cells were incubated with [³H]PGD2 and serial dilutions of AMG-009 (0.001-10 μM) at 25°C for 60 minutes; bound and free ligand were separated by vacuum filtration, and radioactivity was measured using a scintillation counter; Ki values were calculated from competition binding curves using the Cheng-Prusoff equation [1]
2. CYP3A4 time-dependent inhibition assay: Human liver microsomes were preincubated with AMG-009 (0.1-10 μM) in the presence of NADPH for 0, 15, 30, or 60 minutes at 37°C; midazolam was then added as a substrate, and the reaction was incubated for an additional 10 minutes; metabolite formation (1'-hydroxymidazolam) was quantified by LC-MS/MS to determine the percentage of CYP3A4 activity inhibition [3] 3. cAMP inhibition assay for DP receptor: DP-transfected CHO cells were treated with AMG-009 (0.001-10 μM) for 15 minutes, then stimulated with PGD2 (100 nM) and forskolin (10 μM) for 30 minutes; intracellular cAMP levels were measured using a fluorescent immunoassay, and IC50 values for DP antagonism were calculated [1] |
| Cell Assay |
1. CRTH2 calcium mobilization assay: HEK293 cells stably expressing human CRTH2 were seeded in 96-well plates and loaded with a fluorescent calcium indicator for 45 minutes at 37°C; AMG-009 (0.001-10 μM) was added and incubated for 20 minutes, followed by stimulation with PGD2 (100 nM); fluorescence intensity was measured in real-time using a microplate reader, and IC50 values for calcium mobilization inhibition were determined [1]
2. Eosinophil chemotaxis assay: Human peripheral blood eosinophils were isolated and suspended in assay buffer; AMG-009 (0.001-1 μM) was preincubated with eosinophils for 15 minutes, then added to the upper chamber of a transwell plate; PGD2 (100 nM) was added to the lower chamber, and the plate was incubated for 90 minutes at 37°C; migrated eosinophils in the lower chamber were counted by flow cytometry, and chemotaxis inhibition was calculated [1] 3. Th2 cytokine release assay: Human Th2 lymphocytes were polarized from naive CD4+ T cells and cultured with AMG-009 (0.01-1 μM) for 1 hour before stimulation with PGD2 (100 nM) and anti-CD3/CD28 antibodies; culture supernatants were collected after 48 hours, and IL-4/IL-13 levels were quantified by ELISA [1] |
| Animal Protocol |
1. Mouse allergic airway inflammation model: BALB/c mice (6-8 weeks old) were sensitized with ovalbumin (OVA) plus alum on days 0 and 7, then challenged with aerosolized OVA on days 14-16; AMG-009 was formulated in 0.5% methylcellulose + 0.1% Tween 80 and administered orally via gavage at 10, 30, or 100 mg/kg once daily from day 14 to day 20; on day 21, mice were euthanized, bronchoalveolar lavage fluid (BALF) was collected for cytokine analysis, and lung tissues were processed for eosinophil counting via histology [1]
2. Guinea pig bronchoconstriction model: Male Hartley guinea pigs (300-400 g) were anesthetized and instrumented for airway resistance measurement; AMG-009 was dissolved in 10% DMSO/40% PEG400/50% saline and administered intravenously (3 mg/kg) or orally (10 mg/kg) 30 minutes before inhalation of PGD2 (10 μg/mL); airway resistance was measured using a plethysmograph for 60 minutes post-PGD2 challenge [1] |
| ADME/Pharmacokinetics |
1. In male CD-1 mice, after oral administration of AMG-009 (10 mg/kg), the peak plasma concentration (Cmax) at 1 hour (Tmax) was 0.8 μM, the oral bioavailability (F) was 25%, the terminal half-life (t1/2) was 3.2 hours, and the volume of distribution (Vd) was 1.5 L/kg [1]
2. AMG-009 is mainly metabolized in the liver through CYP3A4-mediated oxidation; in human liver microsomes, the main metabolite is the hydroxylated derivative, which accounts for 60% of the total metabolites after 1 hour of incubation [3] 3. In Sprague-Dawley rats, the total clearance (CL) of intravenously administered AMG-009 (5 mg/kg) was 0.4 L/h/kg, with 15% cleared within 48 hours. The original drug is excreted unchanged in urine [1] |
| Toxicity/Toxicokinetics |
1. AMG-009 showed high plasma protein binding rates in mouse, rat, and human plasma (92%, 94%, and 97%, respectively)[1]
2. AMG-009 showed time-dependent inhibition of CYP3A4 with a Ki (inactivation) value of 0.8 μM, while no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, or CYP2D6 was observed at concentrations up to 10 μM[3] 3. Acute toxicity studies in CD-1 mice showed no death or significant toxicity at oral doses up to 500 mg/kg; subchronic toxicity studies (14 days, 100 mg/kg orally daily) showed no significant changes in liver and kidney function indicators (ALT, AST, BUN) or hematological parameters[1] |
| References |
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| Additional Infomation |
1. AMG-009 is a first-generation dual CRTH2 and DP receptor antagonist used to treat Th2-mediated inflammatory diseases such as asthma, allergic rhinitis and atopic dermatitis[1]. 2. The mechanism of action of AMG-009 is to competitively bind to CRTH2 and DP receptors, blocking the PGD2-mediated signaling pathway, thereby inhibiting eosinophil recruitment, Th2 cytokine release and bronchoconstriction[1]. 3. Due to its time-dependent CYP3A4 inhibition, AMG-009 was terminated in the early stages of clinical development, which carries the risk of drug interactions with CYP3A4 substrates (such as statins and antifungal drugs)[3]. 4. [2] noted that AMG-009 was initially developed as a lead compound for optimizing dual CRTH2/DP antagonists, and AMG 853, which has better pharmacokinetic properties and lower CYP3A4 inhibition, was eventually discovered[2].
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| Molecular Formula |
C26H26CL2N2O7S
|
|---|---|
| Molecular Weight |
581.4648
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| Exact Mass |
580.084
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| Elemental Analysis |
C, 53.71; H, 4.51; Cl, 12.19; N, 4.82; O, 19.26; S, 5.51
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| CAS # |
1027847-67-1
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| PubChem CID |
10483360
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| Appearance |
White to light brown solid powder
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| LogP |
7.48
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
38
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| Complexity |
887
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C(C([H])=C([H])C=1S(N([H])C1C([H])=C(C([H])=C([H])C=1OC1C([H])=C([H])C(C([H])([H])C(=O)O[H])=C([H])C=1OC([H])([H])[H])C(N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])=O)(=O)=O)Cl
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| InChi Key |
DKSKRBVXRDGYAS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H26Cl2N2O7S/c1-3-4-11-29-26(33)17-6-9-21(37-22-8-5-16(13-25(31)32)12-23(22)36-2)20(14-17)30-38(34,35)24-10-7-18(27)15-19(24)28/h5-10,12,14-15,30H,3-4,11,13H2,1-2H3,(H,29,33)(H,31,32)
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| Chemical Name |
2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid
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| Synonyms |
AMG-009; AMG 009; AMG009
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7198 mL | 8.5990 mL | 17.1981 mL | |
| 5 mM | 0.3440 mL | 1.7198 mL | 3.4396 mL | |
| 10 mM | 0.1720 mL | 0.8599 mL | 1.7198 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.
 Evaluation of2(AMG 853) and1(AMG 009) in the guinea pig model of PGD2-induced airway constriction.ACS Med Chem Lett. 2011 May 12; 2(5): 326–330. |
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 ACS Med Chem Lett. 2011 May 12; 2(5): 326–330. |
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