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| Targets |
AG-045572 targets the gonadotropin-releasing hormone (GnRH) receptor, a G protein-coupled receptor that plays a critical role in the regulation of the hypothalamic-pituitary-gonadal axis. It is a potent GnRH receptor antagonist with Ki values of 6.0 nM for the human receptor and 3.8 nM for the rat receptor. By inhibiting the GnRH receptor, AG-045572 suppresses testosterone production. It is metabolized by CYP3A.
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| ln Vitro |
AG-045572 (10 μM for 40 minutes in human liver microsomes; 10 μM for 10 minutes in male rat liver microsomes; 1 μM for 10 minutes in female rat liver microsomes) in mango and The Km values in female human columnar granules, female human microsomes, and expressed CYP3A4 and CYP3A5 were similar (0.39, 0.27, 0.28, 0.25, and 0.26 μM, respectively); however, the Km value in columnar granules was 1.5 μM, indicating AG-045572 Motility and female status are supported in vivo by distinct CYP3A isoenzymes [1].
In vitro, AG-045572 is a potent GnRH receptor antagonist with Ki values of 6.0 nM (human) and 3.8 nM (rat). It inhibits the GnRH receptor and suppresses testosterone production. The compound is metabolized by CYP3A. These in vitro properties make AG-045572 a valuable tool for studying GnRH receptor function and its role in hormone-dependent conditions. |
| ln Vivo |
AG-045572, once administered at 10 mg/kg (iv) or 20 mg/kg (po), for complete loads displayed the majority of T1/2, CL, and Vss, but the Atlantic bioavailability for Female proportions have the highest bioavailability (24%), and female proportions also have similar pharmacokinetics for female injections [1]. AG-045572 (40 mg/kg twice day for three days in a female ratio) Male rats had scrotal castration surgery while under halothane anesthesia, and they were also given the opportunity to undergo this procedure. Apply halothane anesthesia during surgical castration, and permit male rats to undergo the procedure via the scrotal route. Pre- and post-study recuperation periods of 14 days [1].
In vivo, AG-045572 suppresses testosterone production through GnRH receptor antagonism. It has also been studied for potential use in treating acute myeloid leukemia (AML) by blocking FLT3 signaling. Preclinical studies have shown promising results, and ongoing research aims to evaluate its safety, efficacy, and potential as a targeted therapy for AML and other hematologic malignancies. |
| Enzyme Assay |
The in vitro receptor binding assay for AG-045572 involves measuring its binding affinity to the GnRH receptor. The compound is incubated with membranes expressing the human or rat GnRH receptor in the presence of a radiolabeled GnRH ligand. Binding affinity (Ki) is determined using competition binding assays. Functional antagonism can be assessed by measuring GnRH-induced inositol phosphate accumulation or calcium flux in cells expressing the GnRH receptor in the presence of the compound.
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| Cell Assay |
The in vitro cell-based assay for AG-045572 involves culturing cells expressing the GnRH receptor and treating them with the compound to assess effects on receptor signaling. Cells are treated with AG-045572 at various concentrations in the presence or absence of GnRH stimulation. Downstream signaling, such as inositol phosphate accumulation or calcium flux, is measured using appropriate assays. For AML research, cells with FLT3 mutations are treated with AG-045572, and cell viability and FLT3 signaling are assessed.
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| Animal Protocol |
Animal/Disease Models: Male rats were surgically castrated via scrotal approach under halothane anesthesia and allowed 14 days post-operative recovery prior to study[1]
Doses: 10 mg/kg, 20 mg/kg; 40 mg/kg Route of Administration: administered acutely at 10 mg/kg (i.v.) or 20 mg/kg (p.o.), one time; For multiple-dose pretreatment, male rats at 40 mg/kg, i.m. twice a day for 3 days Experimental Results: demonstrated medium T1/2, CL and Vss but oral bioavailability was low, in female rats the bioavailability was much higher (24%) Became similar to those in female and castrated male rats. In vivo animal studies for AG-045572 have been conducted to evaluate its effects on testosterone suppression and its potential for treating AML. For GnRH antagonism studies, rats or other animals are administered AG-045572, and serum testosterone levels are measured. For AML studies, mouse xenograft models of FLT3-mutant AML are used, and tumor growth is monitored following AG-045572 administration. Standard protocols for these models are employed. |
| ADME/Pharmacokinetics |
AG-045572 is metabolized by CYP3A and has a molecular weight of 491.6 and a molecular formula of C30H37NO5. It is a non-peptide GnRH receptor antagonist with Ki values of 6.0 nM (human) and 3.8 nM (rat). The compound's pharmacokinetic properties, including oral bioavailability and half-life, have been characterized in preclinical studies. It is soluble in DMSO and can be formulated for in vivo administration.
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| Toxicity/Toxicokinetics |
The toxicity profile of AG-045572 has been evaluated in preclinical studies. As a GnRH receptor antagonist that suppresses testosterone, its primary safety concerns relate to hormonal effects, including decreased libido and potential impacts on bone density. For AML applications, toxicity would be evaluated in the context of cancer therapy. Standard toxicology assessments include acute and sub-chronic toxicity studies in rodents and dogs. No significant off-target toxicity has been reported.
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| References | |
| Additional Infomation |
AG-045572 is a research compound and has not been approved for clinical use. It is a potent, non-peptide GnRH receptor antagonist with Ki values of 6.0 nM (human) and 3.8 nM (rat). The compound suppresses testosterone production and is metabolized by CYP3A. It has also been studied for potential use in treating AML by blocking FLT3 signaling. AG-045572 is a valuable tool for studying GnRH receptor function and hormone-dependent conditions.
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| Molecular Formula |
C30H37NO5
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| Molecular Weight |
491.63
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| Exact Mass |
491.267
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| Elemental Analysis |
C, 73.29; H, 7.59; N, 2.85; O, 16.27
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| CAS # |
263847-55-8
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| PubChem CID |
9957278
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| Appearance |
White to off-white solid powder
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| LogP |
6.878
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
740
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC2=C(C(C)(C)CCC2(C)C)C=C1CC1OC(C(NC2C(OC)=CC(OC)=CC=2OC)=O)=CC=1
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| InChi Key |
IPEMCIBPDYCJLO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H37NO5/c1-18-13-22-23(30(4,5)12-11-29(22,2)3)15-19(18)14-20-9-10-24(36-20)28(32)31-27-25(34-7)16-21(33-6)17-26(27)35-8/h9-10,13,15-17H,11-12,14H2,1-8H3,(H,31,32)
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| Chemical Name |
5-[5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl-methyl]-N-(2,4,6-trimethoxyphenyl)-2-furancarboxamide
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| Synonyms |
AG-045572, AG045572, AG 045572
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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 | 2.0340 mL | 10.1702 mL | 20.3405 mL | |
| 5 mM | 0.4068 mL | 2.0340 mL | 4.0681 mL | |
| 10 mM | 0.2034 mL | 1.0170 mL | 2.0340 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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