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Purity: ≥98%
Darusentan (formerly LU-135252 or HMR-4005) is an endothelin receptor antagonist (ERA)/inhibitor. ERA based on propanoic acid is presently undergoing phase 3 clinical trials to treat resistant hypertension. The ERA (S)-darusentan has a strong affinity for the ET receptor in vascular smooth muscle, which in this preparation primarily consists of ETA receptors. (S)-Darusentan is a strong vasoconstriction inhibitor in both large and small arteries, inhibiting endothelin-induced signaling associated with pro-contractile activity. In aged rats, sodium and potassium excretion is increased by endothelin ETA receptor blockade with darusentan. Strong vasoconstrictor endothelin is frequently upregulated in hypertension. Vascular smooth muscle contains the G-protein coupled endothelin A (ETA) receptor, which mediates endothelin vasoconstriction. It has been demonstrated that endothelin receptor antagonists (ERAs) counteract the vasoconstriction caused by ET.
| Targets |
ET-A
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|---|---|
| ln Vitro |
Darusentan ((S)-Darusentan) exhibits a Ki=13 nM and competes for radiolabeled endothelin binding with single-site kinetics In rat aortic vascular smooth muscle cells (RAVSMs). Darusentan inhibits endothelin-induced vascular contractility with a pA2=8.1±0.14 in isolated endothelium-denuded rat aortic rings. ET-1-induced signaling in cultured RAVSMs is inhibited by darusentan (0.001-1μM)[2].
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| ln Vivo |
Darusentan (30 mg/kg per day orally for weeks 3 and 4) reverses aortic alterations in male Sprague Dawley rats caused by subcutaneous infusion of norepinephrine (2.5 μg/kg per min) for two and four weeks[3].
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| Animal Protocol |
Twenty-four (eight per group) male Sprague Dawley rats weighing 175±200 g
30 mg/kg Administered orally in rat food for weeks 3 and 4 |
| References |
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| Molecular Formula |
C22H22N2O6
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|---|---|---|
| Molecular Weight |
410.43
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| Exact Mass |
393.22
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| Elemental Analysis |
C, 64.38; H, 5.40; N, 6.83; O, 23.39
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| CAS # |
171714-84-4
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
COC1=CC(=NC(=N1)O[C@H](C(=O)O)C(C2=CC=CC=C2)(C3=CC=CC=C3)OC)OC
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| InChi Key |
FEJVSJIALLTFRP-LJQANCHMSA-N
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| InChi Code |
InChI=1S/C22H22N2O6/c1-27-17-14-18(28-2)24-21(23-17)30-19(20(25)26)22(29-3,15-10-6-4-7-11-15)16-12-8-5-9-13-16/h4-14,19H,1-3H3,(H,25,26)/t19-/m1/s1
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| Chemical Name |
(2S)-2-(4,6-dimethoxypyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropanoic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.07 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4365 mL | 12.1823 mL | 24.3647 mL | |
| 5 mM | 0.4873 mL | 2.4365 mL | 4.8729 mL | |
| 10 mM | 0.2436 mL | 1.2182 mL | 2.4365 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00738049 | Recruiting | Drug: darusentan 100 mg | Coronary Artery Disease Endothelial Dysfunction |
K.Lance Gould | June 2009 | Phase 2 |
| NCT00389779 | Completed | Drug: Darusentan Drug: Darusentan Placebo |
Hypertension | Gilead Sciences | September 2006 | Phase 3 |
| NCT00330369 | Completed | Drug: Darusentan Placebo Drug: Darusentan |
Hypertension | Gilead Sciences | June 2006 | Phase 3 |
| NCT00364026 | Completed | Drug: darusentan | Hypertension | Gilead Sciences | June 2004 | Phase 2 |
| NCT00389675 | Terminated | Drug: Darusentan Drug: Guanfacine |
Hypertension | Gilead Sciences | May 2007 | Phase 3 |
Analysis of cell engraftment DPPIV- rats after Ednra blockade with DAR.Hepatology. 2014 Mar; 59(3): 1107–1117. |
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Cell transplantation-induced changes in liver and effects of DAR.Hepatology. 2014 Mar; 59(3): 1107–1117. |
Effects of DAR on cytotoxicity in cultured cells.Hepatology. 2014 Mar; 59(3): 1107–1117. |
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