J-104132
J-104132 (L-753037) is a potent, orally active, selective and competitive ETA/ETB receptor antagonist with Ki of 0.034 nM for ETA and 0.104 nM for ETB receptors. J-104132 inhibits Endothelin-1 (ET-1) (HY-P71446)-induced signaling and vascular contractions in vitro. J-104132 alleviates hypertension, vascular remodeling, and diabetic endothelial dysfunction in vivo by dual ETA/ETB blockade. J-104132 can be used for research on diabetic vascular complications[1][3].
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- CAS No.: 198279-45-7
- Formule: C31H33NO7
- Masse moléculaire:531.60
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
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- Références
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Activité biologique
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ETA 0.034 nM (Ki) |
ETB 0.104 nM (Ki) |
J-104132 potently inhibits ET-1-stimulated phosphatidylinositol hydrolysis (IC50 = 0.059 nM) in human ETA/CHO cells, but fails to stimulate any response by itself at a fully inhibitory concentration (3 nM)[1].
J-104132 (0.001-10 μM) specifically and competitively antagonizes ET-1-induced contractions in rabbit iliac arteries, as it shifts the ET-1 concentration-response curve rightward without affecting the maximal response and does not inhibit contractions induced by KCl or Norepinephrine (HY-13715)[1].
J-104132 (3 nM, 20 min) does not change the Ach (HY-B0282)-induced relaxation in diabetic rats aortae[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| Species | Dose | Route | Note | AUC | CLplasma | MRT | Vd | Cmax | Tmax | F |
|---|---|---|---|---|---|---|---|---|---|---|
| Rat[1] | 0.3 mg/kg | i.v. | AUC0-10h | 246 ng·h/mL | 21.3 mL/min/kg | 1.12 h | 1.27 L/kg | / | / | / |
| Rat[1] | 1 mg/kg | i.v. | AUC0-10h | 936 ng·h/mL | 17.9 mL/min/kg | 0.89 h | 0.97 L/kg | / | / | / |
| Rat[1] | 1 mg/kg | p.o. | AUC0-10h | 408 ng·h/mL | / | 3.10 h | / | 178.0 ng/mL | 0.25 h | 44 % |
| Rat[1] | 10 mg/kg | p.o. | AUC0-10h | 4028 ng·h/mL | / | 2.82 h | / | 1754.3 ng/mL | 0.75 h | / |
| Rat[1] | 3 mg/kg | i.v. | AUC0-10h | 3686 ng·h/mL | 16.7 mL/min/kg | 0.76 h | 0.72 L/kg | / | / | / |
| Rat[1] | 3 mg/kg | p.o. | AUC0-10h | 1252 ng·h/mL | / | 2.89 h | / | 476.8 ng/mL | 0.40 h | 34 % |
J-104132 (0.1, 0.3 and 1 mg/kg, p.o. or i.v., single dose) dose-dependently inhibits the pressor response elicited by ET-1 in SD rats[1].
J-104132 (0.01, 0.03, 0.1 and 0.3 mg/kg/h, i.v., infusion for 2 h) shifts ET-1 dose-response curve to the right in a dose-related manner in dogs[1].
J-104132 (10 mg/kg, i.g., for 2 weeks starting 12 h after balloon injury) decreases the neointima/media ratio in male SD rats and in both male and female ETB-deficient rats, but it has no effect in female wild-type rats[2].
J-104132 (10 mg/kg, p.o., daily for 4 weeks starting 7 weeks after STZ) restores the impaired acetylcholine (ACh)-induced endothelium-dependent relaxation in Streptozotocin (STZ) (HY-13753)-induced diabetic rats[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Male SD rats (6-7 weeks) challenged with big ET-1 (0.5 nmol/kg, i.v.)[1]
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Dosage:1, 3 and 10 mg/kg
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Administration:p.o., single dose
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Result:Almost completely inhibited the pressor response elicited by big ET-1 at 30 min after administration at doses of 1, 3, and 10 mg/kg.
Gradually recovered inhibition of the pressor response elicited by big ET-1 within 3 to 4 h at 1 mg/kg.
Inhibition was maintained for more than 8 hours after administration of the 3 and 10 mg/kg doses.
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Animal Model:Male SD rats (200-400 g) challenged with ET-1 (0.5 nmol/kg, i.v.)[1]
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Dosage:0.1, 0.3 and 1 mg/kg
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Administration:p.o. or i.v., single dose
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Result:Showed dose-related inhibition of ET-1-induced pressor responses after p.o. and i.v. administration.
The relative potencies of J-104132 after p.o. administration were three times less than those after i.v. administration.
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Animal Model:Mongtrl dogs (10-15 kg) challenged with ET-1 (1-100 pmol/min for 30 min into the renal artery)[1]
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Dosage:0.01, 0.03, 0.1 and 0.3 mg/kg/h
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Administration:i.v., infusion for 2 h
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Result:Shifted ET-1 dose-response curve to the right in a dose-related manner.
Shifted the ET-1 dose-response curve approximately 12-fold at 0.03 mg/kg/h.
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Animal Model:Mongtrl dogs (10-15 kg) challenged with ET-1 (1-100 pmol/min for 30 min into the brachial artery)[1]
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Dosage:0.01, 0.03, 0.1 and 0.3 mg/kg/h
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Administration:i.v., infusion for 2 h
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Result:Led to a 15- to 20-fold shift in the dose-response curve at 0.3 mg/kg/h compared with the vehicle.
Shifted the dose-response curve to ET-1 in this vascular bed by more than 20-fold at dose of 0.3 mg/kg/h.
Showed no marked alterations in heart rate, although systemic arterial pressure was observed to slowly decline by approximately 18% over the entire protocol period at the 0.3 mg/kg/h dosage.
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Animal Model:Male and female Wild-type and ETB-deficient rats (12-15 weeks) challenged with balloon injury procedure[2]
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Dosage:10 mg/kg
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Administration:i.g., for 2 weeks starting 12 h after balloon injury
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Result:Markedly decreased the neointima/media ratio in both the wild-type and ETB-deficient male rats.
Markedly decreased the neointima/media ratio in the ETB-deficient female rats but not in the wild-type female rats.
The ETB-deficient rats exhibited significantly increased plasma ET-1 levels, in both males and females compared with the wild-type rats.
Showed no significant differences in ETA or ETB receptor mRNA expression.
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Animal Model:Male and female SD rats (10 weeks) challenged with balloon injury procedure[2]
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Dosage:10 mg/kg
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Administration:i.g., for 2 weeks starting 12 h after balloon injury
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Result:Did not affect body weight, uteri wet weight, or SBP for 2 weeks treatment.
Significantly decreased the neointima/media ratio in the male rats.
Did not affect the neointima/media ratio in female rats.
Significantly increased plasma ET-1 levels compared with vehicle treated group in female SD rats.
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Animal Model:Male Wistar rats (7 weeks) injected with STZ (75 mg/kg)[3]
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Dosage:10 mg/kg
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Administration:p.o., daily for 4 weeks starting 7 weeks after STZ
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Result:Significantly attenuated the impairment of ACh-induced endothelium-dependent relaxation in diabetic rats.
Did not alter plasma glucose, total cholesterol, HDL, VLDL, LDL or triglyceride in diabetic rats.
Revealed that the expression ratio eNOS/GAPDH did not differ among groups.
Reversed the increase of the expression of p22phox mRNA induced by diabetic in rats.
Significantly decreased the elevated level of superoxide anion in the aortae of diabetic rats.
Chemical Information
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CAS No. 198279-45-7
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Masse moléculaire 531.60
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Formule C31H33NO7
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SMILES
O=C(O)[C@H]1[C@H](C(C(C[C@H](C)C(O)=O)=C2)=CC=C2OC)C3=NC(CCCC)=CC=C3[C@@H]1C4=CC=C5OCOC5=C4
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
[1]. Nishikibe M, et al. Pharmacological properties of J-104132 (L-753,037), a potent, orally active, mixed ETA/ETB endothelin receptor antagonist. J Pharmacol Exp Ther. 1999 Jun;289(3):1262-70. [Content Brief]
[2]. Kitada K, et al. Endothelin ETB receptor is involved in sex differences in the development of balloon injury-induced neointimal formation. J Pharmacol Exp Ther. 2011 Feb;336(2):533-9. [Content Brief]
[3]. Kanie N, et al. Effects of chronic administration of the novel endothelin antagonist J-104132 on endothelial dysfunction in streptozotocin-induced diabetic rat. Br J Pharmacol. 2002 Apr;135(8):1935-42. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
J-104132 Related Classifications
HY-10383 Related Classifications
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