AG 045572

GnRH antagonist CAS# 263847-55-8

AG 045572

Catalog No. BCC7464----Order now to get a substantial discount!

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Chemical structure

AG 045572

3D structure

Chemical Properties of AG 045572

Cas No. 263847-55-8 SDF Download SDF
PubChem ID 9957278 Appearance Powder
Formula C30H37NO5 M.Wt 491.62
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 100 mM in DMSO and to 50 mM in ethanol
Chemical Name 5-[(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)methyl]-N-(2,4,6-trimethoxyphenyl)furan-2-carboxamide
SMILES CC1=C(C=C2C(=C1)C(CCC2(C)C)(C)C)CC3=CC=C(O3)C(=O)NC4=C(C=C(C=C4OC)OC)OC
Standard InChIKey IPEMCIBPDYCJLO-UHFFFAOYSA-N
Standard InChI 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AG 045572

DescriptionSelective gonadotropin-releasing hormone (GnRH) receptor antagonist (Ki values are 2.2, 3.8 and 6.0 nM for mouse, rat and human receptors respectively). Suppresses testosterone and luteinising hormone (LH) levels in vivo.

AG 045572 Dilution Calculator

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AG 045572 Molarity Calculator

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Preparing Stock Solutions of AG 045572

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0341 mL 10.1705 mL 20.3409 mL 40.6818 mL 50.8523 mL
5 mM 0.4068 mL 2.0341 mL 4.0682 mL 8.1364 mL 10.1705 mL
10 mM 0.2034 mL 1.017 mL 2.0341 mL 4.0682 mL 5.0852 mL
50 mM 0.0407 mL 0.2034 mL 0.4068 mL 0.8136 mL 1.017 mL
100 mM 0.0203 mL 0.1017 mL 0.2034 mL 0.4068 mL 0.5085 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on AG 045572

AG 045572, also called CMPD1, is a nonpeptidic antagonist of gonadotropin-releasing hormone (GnRH) [1], with Ki values of 6.0 nM and 2.2nM to human and mouse GnRH receptors, respectively [2].

GnRH is a neuroendocrine decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro- Gly-NH2). It is synthesized in the neurovascular terminals of the hypothalamus and hence secreted directly into the hypophyseal portal blood supply in a pulsatile manner. GnRH selectively binds specific receptors on membranes of anterior pituitary gonadotroph cells to stimulate the synthesis and the release of the gonadotropic hormones [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)]. FSH and LH stimulate gametogenesis and gonadal production of sex steroids, respectively [3].

In 293 cells expressing human GnRH receptors, GnRH concentration-dependently increased the accumulation of total [3H] inositol phosphate. This response to GnRH showed an EC50 value of 0.6 ± 0.15 nM (n = 10) with a Hill coefficient of 0.98 ± 0.05. AG 045572 alone did not produce any change in basal levels of inositol phosphates. But AG 045572 concentration-dependently inhibited the response to GnRH. The mean KB ± S.E. of six similar experiments was 25 ± 0.9 nM for AG 045572 at the human receptor. TRH concentration-dependently stimulate the accumulation of total inositol phosphate in GGH3 cells with an EC50 value of 2.4 ± 0.16. AG 045572 at concentrations up to 10 µM had no appreciable inhibition of the accumulation of inositol phosphate stimulated by TRH [3].

After oral administration with AG 045572 at a single dose of 100mg/kg, the concentration of plasma LH in castrated male rats was completely suppressed up to 8 h. 0.5 h after a single intravenous administration with AG 045572 at 10mg/kg, LH levels were suppressed to almost baseline. But this effect lasted for less than 2 h. AG 045572 at a single intravenous dose of 20 mg/kg also reduced concentrations of testosterone in intact male rats [2]. To intact male rats, administration with AG 045572 at a single dose of 100 mg/kg, maintained the suppression of testosterone in the castrate range for 24 hours [4].

References:
[1].  Barnes MJ, Burschka C, Büttner MW, et al. Silicon Analogues of the Nonpeptidic GnRH Antagonist AG-045572: Syntheses, Crystal Structure Analyses, and Pharmacological Characterization. ChemMedChem, 2011, 6(11): 2070-2080.
[2].  Zhu YF, Chen C, Struthers RS. Nonpeptide gonadotropin releasing hormone antagonists. Annu. Rep. Med. Chem, 2004, 39(99): 110.
[3].  Anderes KL, Luthin DR, Castillo R, et al. Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats. Journal of Pharmacology and Experimental Therapeutics, 2003, 305(2): 688-695.
[4].  Herbst KL. Gonadotropin-releasing hormone antagonists. Current opinion in pharmacology, 2003, 3(6): 660-666.

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References on AG 045572

Silicon analogues of the nonpeptidic GnRH antagonist AG-045572: syntheses, crystal structure analyses, and pharmacological characterization.[Pubmed:21953839]

ChemMedChem. 2011 Nov 4;6(11):2070-80.

AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.

Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats.[Pubmed:12606616]

J Pharmacol Exp Ther. 2003 May;305(2):688-95.

Gonadotropin-releasing hormone (GnRH) receptor antagonists have potential in treating numerous hormone-dependent pathologies including cancers of the prostate, breast, and ovary, endometriosis, and fertility disorders. An unmet clinical need exists for an orally available GnRH receptor antagonist. Guided by structure-activity relationships, ligand-based targeted library designs, and biomarker measurements, our discovery efforts have yielded a novel, small molecule GnRH receptor antagonist, 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trim ethoxyphenyl)-2-furamide (CMPD1). CMPD1 bound with low nanomolar affinities to human, rat, and mouse GnRH receptors (6.0, 3.8, and 2.2 nM, respectively). CMPD1 was more than 100-fold selective for GnRH receptors versus various G-protein-coupled receptors and other enzymes and ion channels. In cells expressing recombinant rat GnRH receptors, CMPD1 was a competitive antagonist of GnRH-stimulated increases in extracellular acidification rates in Cytosensor microphysiometer assays. In cells expressing recombinant human GnRH receptors, CMPD1 was a potent inhibitor of GnRH-stimulated total inositol phosphate accumulation. The effects of CMPD1 on circulating levels of luteinizing hormone (LH) and testosterone were studied in castrated and intact male rats, respectively. Intravenous and oral administration of CMPD1 dose dependently suppressed GnRH-mediated elevations of LH in castrated male rats and testosterone in gonad-intact male rats. Moreover, CMPD1, when given at 20 mg/kg i.v. to intact male rats, inhibited the elevations of LH and testosterone stimulated by the superagonist of GnRH, [d-Ala(6), des-Gly(10)]GnRH (GnRH-A). These data suggest that CMPD1 is a potent, selective, orally active GnRH receptor antagonist that may have potential application as a therapeutic agent for treating hormone-dependent cancers and diseases.

Effect of testosterone suppression on the pharmacokinetics of a potent gnRH receptor antagonist.[Pubmed:11883648]

Pharm Res. 2002 Feb;19(2):202-8.

PURPOSE: The expression of cytochrome P450 enzymes (CYPs) in animals and humans is under complex hormonal regulation. Chronic treatment with drugs that alter sex hormone levels such as GnRH receptor agonists or antagonists may affect the expression of hormone-dependent CYPs, and as a result the pharmacokinetics of drugs metabolized by them. METHODS: Enzyme kinetic parameters were obtained by incubating AG-045572 (0.1-30 microM) with human or rat liver microsomes, or expressed CYP3A4 and CYP3A5. The pharmacokinetics of AG-045572 (10 mg/kg i.v. or 20 mg/kg p.o.) were studied in intact male, female, castrated male and male rats pretreated with AG-045572 for 4 days. RESULTS: AG-045572 is metabolized by CYP3A in both rats and humans. The Km values were similar in male and female human, female rat liver microsomes, and expressed CYP3A4 and CYP3A5 (0.39, 0.27, 0.28, 0.25, and 0.26 microM, respectively). The Km in male rat liver microsomes was 1.5 microM, suggesting that in male and female rats AG-045572 is metabolized by different CYP3A isozymes. The oral bioavailability of AG-045572 in intact male rats was 8%, while in female or castrated male rats it was 24%. Pretreatment of intact male rats with AG-045572 i.m. for 4 days resulted in suppression of testosterone to castrate levels, accompanied by an increase in oral bioavailability of AG-045572 to 27%. In the same experiment, the male-specific pulsatile pattern of growth hormone remained unchanged with slightly elevated baseline levels. CONCLUSIONS: The potent GnRH receptor antagonist AG-045572 is metabolized by hormone-dependent CYP3A. As a result, suppression of testosterone by pretreatment with AG-045572 "feminized" its own pharmacokinetics.

Description

Selective GnRH receptor antagonist

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