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Purity: ≥98%
AVE-0991 is a novel, orally bioactive non-peptide mimic and high affinity agonist of angiotensin-(1-7) (IC50 = 21 nM) with important cardioprotective bioactivity. AVE-0991 significantly reduced the perfusion pressure in normal hearts while increasing the heart rate, systolic tension, and the rate at which tension rose and fell (+/-dT/dt).
| Targets |
Ang-(1-7) receptor ( IC50 = 21±35 nM )
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| ln Vitro |
AVE 0991 is a nonpeptide compound that acts on the endothelium in a manner akin to that of Ang-(1-3). The high-affinity binding of [125I]-Ang-(1-7) to bovine aortic endothelial cell membranes is competitive between AVE 0991 and unlabeled Ang-(1–7), with IC50s of 220±280 nM and 21±35 nM, respectively. The release of NO and O2-at peak concentrations by AVE 0991 sodium salt and Ang-(1–7) (both 10 μM) do not differ significantly (NO: 295±20 and 270±25 nM; O2-: 18±2 and 20±4 nM). In contrast to Ang-(1-7)[1], the amount of bioactive NO released by AVE 0991 is approximately five times greater.
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| ln Vivo |
AVE 0991 (0.58 nmol/g) results in a significant reduction of water diuresis in WT mice as compared to animals treated with the vehicle (0.06±0.03 mL versus 0.27±0.05; n = 9 for each group; P<0.01). The antidiuretic action of AVE 0991 (AVE) is linked to a rise in urine osmolality (1669±231.0 mOsm/KgH2O) in comparison to 681.1±165.8 mOsm/KgH2O in mice treated with vehicle; P<0.01). When water is added, the antidiuretic effect of AVE 0991 is eliminated due to the genetic deletion of Mas (0.37±0.10 mL [n=9] versus 0.27±0.03 mL [n=11] in mice treated with AVE 0991). Administration of AVE 0991 (0.58 nmol/g) to water-loaded Swiss mice results in a significantly lower urinary volume than animals treated with a vehicle (0.13±0.05 mL [n=16] versus 0.51±0.04 mL [n=40]; P<0.01)[2]. This observation was also made with C57BL/6 mice on the same subject. AVE-0991 treatment for one week results in a significant decrease in perfusion pressure (56.55±0.86 vs. 68.73±0.69 mmHg in vehicle-treated rats) and an increase in systolic tension (11.40±0.05 vs. 9.84±0.15 g in vehicle-treated rats).It also causes a rise in the rate of tension (+dT/dt; 184.30±0.50 vs. 155.20±1.97 g/s in vehicle-treated rats), a fall in the rate of tension (dT/dt; 179.60±1.39 vs. 150.80±2.42 g/s in vehicle-treated rats). Notably, rats treated with vehicles showed a marginally higher heart rate (HR) of 220.40±0.71 beats/min as opposed to 214.20±0.74 beats/min[3].
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| Cell Assay |
Rat Mas cDNA is stably transfected into Chinese hamster ovary (CHO) cells and monkey kidney (COS) cells using a cytomegalovirus promoter. Neomycin is used to select the transfected cells. Either with or without AVE 0991 (AVE, 10-10 to -5 mol/L), 125I-Ang-(1-7) (0.5×10-9 mol/L) is cultured in 24-well plates for 60 minutes at 4°C in 0.3 mL of serum-free medium (DMEM) supplemented with 0.2% BSA, 0.005% bacitracin, 0.1 mol/L PMSF, and 0.5 mol/L orthophenanthroline with Mas-transfected COS cells. Following two cold, serum-free DMEM washes, 0.1% Triton X-100 is used to agitate the cells. A gamma counter is used to measure bound radioactivity. Using 2×10-9 mol/L rhodamine-labeled Ang-(1-7) in the presence or absence of AVE (10-6 mol/L), CV11974 (10-6 mol/L), or PD123319 (10-6 mol/L), binding of rhodamine-Ang-(1-7) in Mas-transfected CHO cells is carried out under equal circumstances. A concentration of 10-6 mol/L of Ang-(1-7) is required to calculate NSB [1].
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| Animal Protocol |
Mice: The mice used are male Swiss mice, male Mas-KO (Mas-/-) mice on the pure genetic background C57BL/6, and male WT C57BL/6 control mice (Mas+/+). In conscious mice, an intraperitoneal water injection (0.05 mL/g of body weight [BW]) causes water diuresis. Predetermined volumes of water load (0.01 mL/g BW) are used to administer drugs in the same injection. In the first set of experiments, either vehicle for AVE 0991 (10 μM KOH, 0.01 mL/g; n = 9 control; n = 9 Mas-KO) or 0.58 nmol/g AVE 0991 (n = 9 control; n = 11 Mas-KO mice) is administered to WT (C57BL/6, control group) or Mas-KO mice. Swiss mice in the second set receive the following treatments: (1) vehicle (n = 36); (2) 0.58 nmol/g AVE 0991 (n = 16); (3) 46 pmol/g Ang-(1-7) antagonist A-779 (n = 4); (4) 2 nmol/g DuP-753 or CGP 48933 (n = 5); (5) 2 nmol/g AT2 receptor antagonists PD123319 or PD123177 (n = 9); (6) AVE 0991 combined with A-779; (7) AVE 0991 combined with DuP-753 or CGP 48933 (n = 4 for each); (8) or AVE 0991 combined with PD123319 (n = 5) or PD123177 (n = 4). The dosage of AVE 0991 is determined by means of pilot studies conducted on Swiss mice.
Rats: We use male Wistar rats weighing between 250 and 300 grams. Rats are given AVE-0991 (1 mg/kg, n = 9) or vehicle (0.9% NaCl, n = 11) orally via gavage. |
| References |
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| Molecular Formula |
C29H32N4O5S2
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|---|---|
| Molecular Weight |
580.71818
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| Exact Mass |
580.181
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| Elemental Analysis |
C, 59.98; H, 5.55; N, 9.65; O, 13.78; S, 11.04
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| CAS # |
304462-19-9
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| Related CAS # |
AVE 0991 sodium salt; 306288-04-0
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| PubChem CID |
9851724
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.639
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
40
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| Complexity |
931
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=S(C1=C(C2=CC=C(CN3C(C=O)=C(OC)N=C3C4=CC=CC=C4)C=C2)C=C(CC(C)C)S1)(NC(NCC)=O)=O
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| InChi Key |
QTOZBSNPDCWHPV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H32N4O5S2/c1-5-30-29(35)32-40(36,37)28-24(16-23(39-28)15-19(2)3)21-13-11-20(12-14-21)17-33-25(18-34)27(38-4)31-26(33)22-9-7-6-8-10-22/h6-14,16,18-19H,5,15,17H2,1-4H3,(H2,30,32,35)
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| Chemical Name |
1-ethyl-3-[3-[4-[(5-formyl-4-methoxy-2-phenylimidazol-1-yl)methyl]phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylurea
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| Synonyms |
AVE0991; AVE0991; AVE-0991
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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 |
| 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) |
DMSO: ~41.7 mg/mL (~71.8 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.31 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 25.0 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: 2.5 mg/mL (4.31 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.31 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7220 mL | 8.6100 mL | 17.2200 mL | |
| 5 mM | 0.3444 mL | 1.7220 mL | 3.4440 mL | |
| 10 mM | 0.1722 mL | 0.8610 mL | 1.7220 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.
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