product name PRX-08066
Description: PRX-08066 is a potent and selective 5-HT2B receptor antagonist with IC50 of 3.4 nM, it prevents the severity of pulmonary arterial hypertension in the MCT rat model. PRX-08066 reduces monocrotaline-induced pulmonary arterial hypertension and right ventricular hypertrophy in rats. In the 5-HT2B expressing SI-NET cell line, KRJ-I, PRX-08066 inhibited proliferation and 5-HT secretion and decreased ERK1/2 phosphorylation and profibrotic growth factor synthesis and secretion (transforming growth factor beta 1 [TGFbeta1], connective tissue growth factor [CTGF] and fibroblast growth factor [FGF2]).
References: J Pharmacol Exp Ther. 2010 Aug;334(2):364-72; Cancer. 2010 Jun 15;116(12):2902-12
401.89
Formula
C19H17ClFN5S
CAS No.
866206-54-4
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 7 mg/mL
Water:
Ethanol:
Solubility (In vivo)
Synonyms
MT500
other peoduct :
| In Vitro |
In vitro activity: PRX-08066 inhibits 5-HT-induced mitogen-activated protein kinase activation with IC50 of 12 nM and markedly reduces thymidine incorporation with IC50 of 3 nM in Chinese hamster ovary cells expressing the human 5-HT2BR, which suggests that PRX-08066 can potentially inhibit the pathologic 5-HT-induced vascular muscularization associated with PAH. PRX-08066 inhibits cell proliferation with IC50 of 0.46 nM and with a maximum inhibition of 20% and 5-HT secretion with IC50 of 6.9 nM with a maximum inhibition of 30% in the 5-HT(2B) expressing SI-NET cell line, KRJ-I. PRX-08066 inhibits isoproterenol-stimulated 5-HT release with IC50 of 1.25 nM and a maximum inhibition of 60% in NCI-H720 cells. 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. PRX-08066 decreases level of transcripts for Ki67 (84%) as well as Ki67 protein (36.8%) associated with an increase in caspase 3 transcript levels in KRJ-I cells. PRX-08066 decreases level of transcripts of TGFβ1, FGF2 and TPH1 in KRJ-I cells. PRX-08066 significantly increases the number of dead cells (34%) compared with untreated controls in KRJ-I cells. PRX-08066 causes a significant increase in dead/caspase 3 positive cells (76%) and caspase 3 activity (52%) in HEK293 cells. Kinase Assay: 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). After 24 hours, mitochondrial activity is measured after adding MTT (3-[4,5-dimethylthiazol-2-ly]-2.5-diphenyltetrazolium bromide: 0.5mg/mL per well) for 3 hours. The optical density is read photospectrometrically at 595 nm using a microplate reader. 29 Results are normalized to control (unstimulated cells) and the effective half-maximal concentrations calculated. |
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| In 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. PRX-08066 also significantly reduces right ventricle (RV)/body weight and RV/left ventricle + septum, compared with MCT-treated rats. PRX-08066 significantly attenuates the elevation in pulmonary artery pressure and RV hypertrophy and maintains cardiac function. PRX-08066 significantly reduces the hypoxia-dependent increase in right ventricular systolic pressure in both rats and mice without affecting the systemic mean arterial pressure in the animals. PRX-08066 (100 mg/kg) significantly inhibits both right ventricular systolic pressure and right ventricular/left ventricular +septum weight elevations in rats. PRX-08066 (30 mg/kg) inhibits right ventricular systolic pressure and monocrotaline-induced ERK phosphorylation in whole lung homogenates in rats. |
| Animal model | Male Sprague-Dawley rats |
| Formulation & Dosage | Dissolved in 0.5% methylcellulose (w/v); 100 mg/kg; Oral gavage |
| References | J Pharmacol Exp Ther. 2010 Aug;334(2):364-72; Cancer. 2010 Jun 15;116(12):2902-12 |
