PRX-08066 Maleic acid 866206-55-5_5-HT Receptor_GPCR & G Protein_Signaling Pathways_Products

PRX-08066 maleic acid (MT500; MT-500; PRX 08066; PRX08066), the maleic acid salt of PRX08066, is a novel, potent and selective 5-HT2B receptor antagonist with important biological activity. It inhibits 5-HT2B with an IC50 of 3.4 nM. It inhibits 5-HT2B with an IC50 of 3.4 nM. In the MCT rat model, PRX-08066 reduces the severity of pulmonary arterial hypertension. In rats, PRX-08066 decreases right ventricular hypertrophy and pulmonary arterial hypertension brought on by monocrotaline. In the SI-NET cell line KRJ-I that expressed 5-HT2B, PRX-08066 suppressed proliferation and secretion of 5-HT while also lowering phosphorylation of ERK1/2 and profibrotic growth factor synthesis and secretion (fibroblast growth factor [FGF2], connective tissue growth factor [CTGF], and transforming growth factor beta 1 [TGFbeta1]).

Physicochemical Properties

Molecular Formula

C23H21CLFN5O4S

Molecular Weight

517.96

Exact Mass

517.098

CAS #

866206-55-5

Related CAS #

PRX-08066; 866206-54-4

PubChem CID

51348293

Appearance

Typically exists as solid at room temperature

LogP

4.154

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

670

Defined Atom Stereocenter Count

SMILES

C(/C(=O)O)=C/C(=O)O.N(C1CCN(CC2C=CC(F)=C(C#N)C=2)CC1)C1=NC=NC2SC(=CC1=2)Cl

InChi Key

RPYIKXHIQXRXEM-BTJKTKAUSA-N

InChi Code

InChI=1S/C19H17ClFN5S.C4H4O4/c20-17-8-15-18(23-11-24-19(15)27-17)25-14-3-5-26(6-4-14)10-12-1-2-16(21)13(7-12)9-22;5-3(6)1-2-4(7)8/h1-2,7-8,11,14H,3-6,10H2,(H,23,24,25);1-2H,(H,5,6)(H,7,8)/b;2-1-

Chemical Name

(Z)-but-2-enedioic acid;5-[[4-[(6-chlorothieno[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]methyl]-2-fluorobenzonitrile

Synonyms

PRX-08066; MT500; MT-500; PRX 08066; PRX08066; MT 500

HS Tariff Code

2934.99.9001

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)

Biological Activity

Targets

5-HT2B ( IC50 = 3.4 )

ln Vitro

In vitro activity: PRX-08066 suppresses thymidine incorporation with an IC50 of 3 nM and inhibits 5-HT-induced mitogen-activated protein kinase activation with an IC50 of 12 nM in Chinese hamster ovary cells expressing the human 5-HT2BR, indicating that PRX-08066 may be able to prevent the pathologic 5-HT-induced vascular muscularization linked to PAH.[1] In the 5-HT(2B) expressing SI-NET cell line, KRJ-I, PRX-08066 inhibits cell proliferation with an IC50 of 0.46 nM and a maximum inhibition of 20%; in 5-HT secretion, it has an IC50 of 6.9 nM and a maximum inhibition of 30%; in NCI-H720 cells, PRX-08066 inhibits isoproterenol-stimulated 5-HT release with an IC50 of 1.25 nM and a maximum inhibition of 60%. PRX-08066 (0.5 nM) significantly inhibits ERK phosphorylation in KRJ-I cells. PRX-08066 inhibits TGFβ1, CTGF and FGF2 transcription and secretion in KRJ-I cells. In KRJ-I cells, PRX-08066 increases the transcript levels of caspase 3 and decreases the levels of Ki67 (84%) and Ki67 protein (36.8%). In KRJ-I cells, PRX-08066 reduces the amount of TGFβ1, FGF2, and TPH1 transcripts. In KRJ-I cells, PRX-08066 considerably raises the percentage of dead cells (34%) when compared to untreated controls. In HEK293 cells, PRX-08066 significantly raises caspase 3 activity (52%) and the proportion of dead/caspase 3 positive cells (76%).[2]

ln Vivo

PRX-08066 (100 mg/kg) treated groups demonstrates less right ventricular hypertrophy and septal flattening than the monocrotaline control group in rats. PRX-08066 significantly reduces peak pulmonary artery pressure at 50 mg/kg and 100 mg/kg compared with monocrotaline control rats. In comparison to rats treated with MCT, PRX-08066 also significantly lowers the right ventricle (RV)/body weight and the RV/left ventricle + septum. While maintaining cardiac function, PRX-08066 significantly reduces the increase in pulmonary artery pressure and RV hypertrophy. In both rats and mice, PRX-08066 dramatically lowers the hypoxia-dependent rise in right ventricular systolic pressure without changing the animals' systemic mean arterial pressure. PRX-08066 (100 mg/kg) prevents ERK phosphorylation induced by monocrotaline in whole lung homogenates as well as right ventricular systolic pressure in rats.[3]

Cell Assay

5×10³ cells/mL, seeds in 96-well plates at 100 μL (4 plates/experimental condition) are stimulated with PRX-08066 (0.1 μM to 100 nM: n = 6 wells/concentration). Following a 24-hour period, mitochondrial activity is assessed by adding 3-[4,5-dimethylthiazol-2-ly]-2.5-diphenyltetrazolium bromide (0.5 mg/mL per well) and waiting three hours. A microplate reader is used to measure the optical density photospectroscopically at 595 nm. 29 Results are normalized to control (unstimulated cells) and the effective half-maximal concentrations calculated.

Animal Protocol

Dissolved in 0.5% methylcellulose (w/v); 100 mg/kg; Oral gavage

Male Sprague-Dawley rats

References

[1]. J Pharmacol Exp Ther . 2010 Aug;334(2):364-72.

[2]. Cancer . 2010 Jun 15;116(12):2902-12.

Solubility Data

Solubility (In Vitro)

DMSO: ~104 mg/mL (~200.8 mM)

Water: ~104 mg/mL (~200.8 mM)

Ethanol: ~98 mg/mL (~189.2 mM)

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
(e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).
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)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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).
Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.9307 mL	9.6533 mL	19.3065 mL
	5 mM	0.3861 mL	1.9307 mL	3.8613 mL
	10 mM	0.1931 mL	0.9653 mL	1.9307 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.

PeptideDB

PRX-08066 Maleic acid 866206-55-5

CAS No.: 866206-55-5

Physicochemical Properties

Biological Activity

Solubility Data