Urea, N-[2-[4-hydroxy-4-(phenylMethyl)-1-piperidinyl]ethyl]-N'-(2-Methyl-4-quinolinyl)-

Product NameUrea, N-[2-[4-hydroxy-4-(phenylMethyl)-1-piperidinyl]ethyl]-N'-(2-Methyl-4-quinolinyl)-
CAS540769-28-6
MFC25H30N4O2
MW418.53
EINECS
MOL File540769-28-6.mol

Chemical Properties

Boiling point	612.9±55.0 °C(Predicted)
Density	1.235±0.06 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	DMF: 10 mg/ml; DMSO: 10 mg/ml; DMSO:PBS (pH 7.2) (1:1): 0.5 mg/ml; Ethanol: 0.5 mg/ml
form	A crystalline solid
pka	12.95±0.43(Predicted)
color	White to pink
InChI	1S/C25H30N4O2/c1-19-17-23(21-9-5-6-10-22(21)27-19)28-24(30)26-13-16-29-14-11-25(31,12-15-29)18-20-7-3-2-4-8-20/h2-10,17,31H,11-16,18H2,1H3,(H2,26,27,28,30)
InChIKey	WYJCYXOCHXWTHG-UHFFFAOYSA-N
SMILES	N3(CCC(CC3)(O)Cc4ccccc4)CCNC(=O)Nc1c2c(nc(c1)C)cccc2

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids

Usage And Synthesis

Description

Palosuran is an antagonist of the urotensin II receptor (UTR; IC₅₀s = 3.6 and 1,475 nM for CHO cell membranes expressing human and rat recombinant receptors, respectively). It inhibits contraction of isolated rat aortic rings induced by urotensin II (Item Nos. 24711 | 24753) in a concentration-dependent manner. Palosuran (300 mg/kg twice per day) reduces plasma endothelin-1 , urotensin II, and TGF-β1 levels, as well as the main pulmonary arterial pressure and right ventricular hypertrophy index in a rat model of pulmonary arterial hypertension (PAH) induced by monocrotaline . Palosuran (300 mg/kg per day) reduces serum glucose, cholesterol, and triglyceride levels and increases survival in a rat model of diabetes induced by streptozotocin (STZ; ). It also decreases albuminuria and global kidney lesion scores in STZ-induced diabetic rats.

Uses

Palosuran (ACT-058362) is a potent, selective, and orally active antagonist of urotensin II receptor, with an IC50 of 3.6 nM for CHO cell membranes expressing human recombinant receptors. Palosuran can improves pancreatic and renal function in diabetic rats[1][2].

in vivo

ACT-058362 (10 mg/kg/h; i.v.) fully prevents the decrease in renal blood flow after ischemia in rats without decreasing blood pressure^[1].
Palosuran (300 mg/kg/d; p.o. for 16 weeks) improves the survival, increases insulin, and slows the increase in glycemia, glycosylated hemoglobin, and serum lipids in streptozotocin-induced diabetic rats^[2].

Animal Model:	Male Wistar rats with renal ischemia and reperfusion^[1]
Dosage:	20 mg/kg/h for 135 min
Administration:	I.v. (continuous infusion) for 135 min
Result:	Restored renal blood flow to baseline values at 30 min after reperfusion and by 60 min increased renal blood flow by 12% above baseline values. Did not significantly alter mean arterial blood pressure (MAP) and heart rate (HR).

References

[1] Clozel M, et al. Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin System. J Pharmacol Exp Ther. 2004 Oct;311(1):204-12. DOI:10.1124/jpet.104.068320
[2] Clozel M, et al. The urotensin-II receptor antagonist palosuran improves pancreatic and renal function in diabetic rats. J Pharmacol Exp Ther. 2006 Mar;316(3):1115-21. DOI:10.1124/jpet.105.094821

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