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Losartan (DuP-753) is a potent, selective, and non-peptide angiotensin II receptor antagonist, it competes with angiotensin II for binding to AT1 receptors with IC50 of 20 nM. Losartan reduces the jugular vein and rabbit aorta's ability to contract due to angiotensin II (pA2 = 8.27). It is a medication that is taken orally to treat hypertension. Monkeys with diet-induced hypercholesterolemia show marked increases in plasma angiotensin II and angiotensin-(1–7) in response to losartan (180 mg/d).
| Targets |
AT1 Receptor
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|---|---|
| ln Vitro |
Losartan competes with angiotensin II's ability to bind to AT1 receptors in vitro; the concentration that prevents 50% of this binding (IC50) is 20 nmol/L[1]. In VSMCs, losartan increases AMPK phosphorylation in a dose- and time-dependent manner. It also raises the phosphorylation of LKB1, an AMPK upstream kinase, and ACC, a significant downstream target protein in the AMPK signaling cascade. While p27 expression levels remain unchanged, losartan causes a time-dependent increase in p53 and p21 expression. Losartan inhibits the expression of cyclin D and cyclin E, which are necessary for the progression of the cell cycle, as well as Ang II-induced Rb phosphorylation. Therefore, G0/G1 cell cycle arrest—which is reversible by AMPK inhibition, such as compound C or AMPK siRNA, but not by apoptosis—is the mechanism by which losartan suppresses growth[2].
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| ln Vivo |
Losartan has a major active metabolite, EXP 3174. EXP3174 is 10–20 times more potent and acts for a longer period of time when administered intravenously than losartan. EXP 3174 has a very low oral bioavailability, though. When dosed at 50–100 mg/d, losartan has a bioavailability of roughly 33%, a half-life of 2 hours (6–9 hours), and a rate of protein binding of 98.7%[1]. In hypertensive rats, treatment with losartan reduces the loss of endothelial progenitor cells (EPCs) in terms of both quantity and function[3].
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| Cell Assay |
The MTT assay is used to quantify the viability and proliferation of cells. In a 96-well plate, 5000 cells are seeded with 200 μL media per well for the assay. After allowing the cells to attach over night, the medium is suctioned out. After adding MTT to serum-free medium at a concentration of 1 mg/mL, the mixture is incubated for 4 hours at 37°C. To dissolve the formazan crystals, 100 μL of DMSO is added after the MTT solution is removed. Then, using a microplate reader, absorbance is measured at 570 nm and 600 nm as references. Thus, the variation in absorbance is related to the degree of cell survival.
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| Animal Protocol |
Mice of the wild type mate with female Fbn1C1039G/+ mice at predetermined times. Ocular losartan (0.6 g/L in drinking water; n = 10), propranolol (0.5 g/L; n = 6), or placebo (n = 12) is administered to pregnant female Fbn1C1039G/+ mice at 14.5 days post-coitum. Up until the age of ten months, therapy is administered during lactation and following weaning. These methods are applied to the sacrifice and examination of mice. In MFS, the current, albeit contentious, standard of care for modulating abnormal growth of the aortic root is β-adrenergic receptor blockade; propranolol and losartan are the comparison drugs. At 7 weeks of age, oral losartan (0.6 g/L in drinking water; n = 5), propranolol (0.5 g/L; n = 7), or a placebo (n = 10) is administered to wild-type and Fbn1C1039G/+ mice. Following six months of oral treatment, mice are sacrificed.
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| References |
| Molecular Formula |
C22H23CLN6O
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|---|---|
| Molecular Weight |
422.91
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| Exact Mass |
422.16
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| Elemental Analysis |
C, 62.48; H, 5.48; Cl, 8.38; N, 19.87; O, 3.78
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| CAS # |
114798-26-4
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| Related CAS # |
Losartan Carboxylic Acid; 124750-92-1; Losartan-d4 (carboxylic acid); 1246820-62-1; Losartan potassium; 124750-99-8; Losartan-d4; 1030937-27-9; Losartan-d3 Carboxylic Acid; 1189729-40-5; Losartan-d2; 1030936-22-1; Losartan-d9; 1030937-18-8
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| Appearance |
Solid powder
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| SMILES |
CCCCC1=NC(=C(N1CC2=CC=C(C=C2)C3=CC=CC=C3C4=NNN=N4)CO)Cl
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| InChi Key |
PSIFNNKUMBGKDQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H23ClN6O/c1-2-3-8-20-24-21(23)19(14-30)29(20)13-15-9-11-16(12-10-15)17-6-4-5-7-18(17)22-25-27-28-26-22/h4-7,9-12,30H,2-3,8,13-14H2,1H3,(H,25,26,27,28)
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| Chemical Name |
[2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol
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| Synonyms |
DUP 89; DUP-89; DUP89
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| HS Tariff Code |
2934.99.03.00
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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: ≥ 100 mg/mL (~236.5 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.92 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 (4.92 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 | 2.3646 mL | 11.8228 mL | 23.6457 mL | |
| 5 mM | 0.4729 mL | 2.3646 mL | 4.7291 mL | |
| 10 mM | 0.2365 mL | 1.1823 mL | 2.3646 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 |
| NCT03632213 | Active Recruiting |
Drug: Losartan Drug: Placebo |
MPS IV A MPS VI |
Hospital de Clinicas de Porto Alegre |
November 7, 2018 | Phase 2 |
| NCT03563248 | Active Recruiting |
Drug: FOLFIRINOX Drug: Losartan |
Pancreatic Cancer | Massachusetts General Hospital | August 10, 2018 | Phase 2 |
| NCT04815902 | Active Recruiting |
Drug: Fisetin Drug: Losartan Drug: Placebo - Losartan |
Osteoarthritis, Knee | Steadman Philippon Research Institute |
May 18, 2021 | Phase 1 Phase 2 |
| NCT03864042 | Active Recruiting |
Drug: losartan Drug: caffeine |
Advanced Solid Tumors Metastatic Melanoma |
Pfizer | January 2, 2018 | Phase 1 |
| NCT05576155 | Active Recruiting |
Drug: Compound 21 Drug: Compound 21 + losartan |
Sex Differences | Anna Stanhewicz, PhD | January 2013 | Early Phase 1 |
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