Losartan

Names

[ Name ]:
Losartan

[Synonym ]:
2-Butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol
nyl)-4-yl)methyl)
1H-imidazole-5-methanol, 2-butyl-4-chloro-1-2'-(1H-tetrazol-5-yl)1,1'-biphenyl-4-ylmethyl-
Lorzaar
Compound 89
(2-Butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol
1H-Imidazole-5-methanol, 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
LOS
2-Butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol
(2-butyl-4-chloro-1-{2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl}-1H-imidazol-5-yl)methanol
Losartan
dup89
(2-Butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)-4-biphenylyl]methyl}-1H-imidazol-5-yl)methanol
2-n-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole
MFCD00865831

Biological Activity

[Description]:

Losartan is an angiotensin II receptor antagonist, competing with the binding of angiotensin II to AT1 receptors with IC50 of 20 nM.

[Related Catalog]:

Signaling Pathways >> GPCR/G Protein >> Angiotensin Receptor

Research Areas >> Cardiovascular Disease

[Target]

IC50: 20 nM (angiotensin II)

[In Vitro]

Losartan competes with the binding of angiotensin II to AT1 receptors. The concentration that inhibits 50% of the binding of angiotensin II (IC50) is 20 nM[1]. Losartan (40 μM) affects ISC but prevents the effect of ANGII on ISC[2]. Losartan significantly reduces Ang II-mediated cell proliferation in endometrial cancer cells. The combination of losartan and anti-miR-155 has a significantly greater antiproliferative effect compared to each drug alone[3].

[In Vivo]

Losartan (0.6 g/L, p.o.) -treated Fbn1C1039G/+ mice show a reduction in distal airspace caliber relative to placebo-treated Fbn1C1039G/+ animals. The doses of losartan and propranolol are titrated to achieve comparable hemodynamic effects. Analysis of pSmad2 nuclear staining reveals that losartan antagonizes TGF-β signaling in the aortic wall of Fbn1C1039G/+ mice. Losartan can improve disease manifestations in the lungs, an event that cannot plausibly relate to improved hemodynamics[4]. Losartan (10 mg/kg, intraarterial injection) increases blood angiotensin levels four- to sixfold. Losartan (10 mg/kg, i.p.) increases plasma renin levels 100-fold; plasma angiotensinogen levels decreases to 24% of control; and plasma aldosterone levels are unchanged[5].

[Cell Assay]

An MTT assay is used to measure cell proliferation and viability. For the assay, 5000 cells in 200 μL media per well are seeded in a 96 well plate. After overnight incubation to allow for cell attachment, the medium is removed by suction. MTT at 1 mg/mL concentration in serum-free medium is added and then incubated for 4 h at 37°C. After removal of MTT solution, 100 μL of DMSO is added to dissolve formazan crystals. Absorbance at 570 nm and at 600 nm as a reference is then measured using a microplate reader. The difference in absorbance is thus relative to the extent of cell survival.

[Animal admin]

Female Fbn1C1039G/+ mice undergo timed matings with wild-type male mice. At 14.5d post-coitum, pregnant female Fbn1C1039G/+ mice are treated with oral losartan (0.6 g/L in drinking water; n=10), propranolol (0.5 g/L; n=6) or placebo (n=12). Therapy is continued throughout lactation and after weaning until 10 months of age. Mice are sacrificed and examined using the techniques described above. Propranolol is used for comparison with losartan because β-adrenergic receptor blockade is the current albeit controversial standard of care to modulate abnormal growth of the aortic root in MFS. Beginning at 7 weeks of age, wild-type and Fbn1C1039G/+ mice are treated with oral losartan (0.6 g/L in drinking water; n=5), propranolol (0.5 g/L; n=7) or placebo (n=10). Mice are continued on oral therapy for 6 months and then sacrificed.

[References]

[1]. Burnier, M. Angiotensin II type 1 receptor blockers. Circulation, 2001. 103(6): p. 904-12.

[2]. Ashry, O., et al. Evidence for expression and function of angiotensin II receptor type 1 in pulmonary epithelial cells. Respir Physiol Neurobiol, 2014.

[3]. Choi, C.H., et al. Angiotensin II type I receptor and miR-155 in endometrial cancers: synergistic antiproliferative effects of anti-miR-155 and losartan on endometrial cancer cells. Gynecol Oncol, 2012. 126(1): p. 124-31.

[4]. Habashi, J.P., et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science, 2006. 312(5770): p. 117-21.

[5]. Campbell, D.J., et al. Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme. J Cardiovasc Pharmacol, 1995. 26(2): p. 233-40.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Boiling Point ]:
682.0±65.0 °C at 760 mmHg

[ Melting Point ]:
183-184ºC

[ Molecular Formula ]:
C₂₂H₂₃ClN₆O

[ Molecular Weight ]:
422.911

[ Flash Point ]:
366.3±34.3 °C

[ Exact Mass ]:
422.162201

[ PSA ]:
92.51000

[ LogP ]:
3.57

[ Vapour Pressure ]:
0.0±2.2 mmHg at 25°C

[ Index of Refraction ]:
1.681

Toxicological Information

CHEMICAL IDENTIFICATION

RTECS NUMBER :: NI6732550

CHEMICAL NAME :: 1H-Imidazole-5-methanol, 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'- biphenyl)-4-yl)methyl)-

CAS REGISTRY NUMBER :: 114798-26-4

LAST UPDATED :: 199807

DATA ITEMS CITED :: 2

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Human - woman

DOSE/DURATION :: 42 mg/kg/6W-I

TOXIC EFFECTS :: Gastrointestinal - hypermotility, diarrhea Kidney, Ureter, Bladder - changes in tubules (including acute renal failure, acute tubular necrosis) Kidney, Ureter, Bladder - urine volume decreased

REFERENCE :: AIMEAS Annals of Internal Medicine. (American College of Physicians, 4200 Pine St., Philadelphia, PA 19104) V.1- 1927- Volume(issue)/page/year: 124,775,1996

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Human - man

DOSE/DURATION :: 17500 ug/kg/17W-I

TOXIC EFFECTS :: Sense Organs and Special Senses (Taste) - change in function

REFERENCE :: LANCAO Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- Volume(issue)/page/year: 347,471,1996

Safety Information

[ Hazard Codes ]:
Xi: Irritant;

[ Risk Phrases ]:
R36/37/38

[ Safety Phrases ]:
S8-S43-S36/37-S22

[ RIDADR ]:
3278

[ WGK Germany ]:
3

[ Packaging Group ]:
III

[ Hazard Class ]:
4.3

[ HS Code ]:
2942000000

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2933990090

[ Summary ]:
2933990090. heterocyclic compounds with nitrogen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%