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EXP 3174

Names

[ CAS No. ]:
124750-92-1

[ Name ]:
EXP 3174

[Synonym ]:
2-n-butyl-5-chloro-3-[2'-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid
E-3174
Losartan carboxylic acid
1H-Imidazole-5-carboxylic acid, 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
2-Butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)-4-biphenylyl]methyl}-1H-imidazole-5-carboxylic acid
Carboxylosartan
2-Butyl-4-chloro-1-{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid
1H-Imidazole-5-carboxylic acid,2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)
Exp3174
EXP-3174

Biological Activity

[Description]:

Losartan Carboxylic Acid (E-3174), an active carboxylic acid metabolite of Losartan, is an angiotensin II receptor type 1 (AT1) antagonist. The Ki values are 0.97, 0.57, 0.67 nM for rat AT1B/AT1A and human AT1, respectively. Losartan Carboxylic Acid blocks the angiotensin II-induced responses in vascular smoothmuscle cells (VSMC). Losartan Carboxylic Acid elevates plasma renin activities and reduces mean arterial pressure[1][2][3][4].

[Related Catalog]:

Research Areas >> Cardiovascular Disease
Signaling Pathways >> GPCR/G Protein >> Angiotensin Receptor

[Target]

Angiotensin II receptor type 1[1]


[In Vitro]

The specific binding of [125I]-angiotensin II to VSMC is inhibited by Losartan Carboxylic Acid (E-3174) with an IC50 of 1.1 nM. Losartan Carboxylic Acid abolishes the angiotensin II-induced formation of inositolphosphates in VSMC. Losartan Carboxylic Acid inhibits the angiotensin II-induced elevation of intracellular cytosolic Ca2+ concentration with an IC50 of 5 nM. Losartan Carboxylic Acid is more effective than losartan in blocking the angiotensin II-induced increase in Egr-1 mRNA. Losartan Carboxylic Acid inhibits the angiotensin II-induced cell protein synthesis with an IC50 of 3 nM[1].

[In Vivo]

Losartan Carboxylic Acid (E-3174) (0.1 mg/kg; i.v. followed by 0.02 mg/kg/h for 5.5 h) induces a similar level of inhibition (87±4%) of the pressor responses to angiotensin I[3]. Intravenous Losartan Carboxylic Acid (0.1 mg/kg+0.01 mg/kg/min) is infused in anesthetized dogs with recent (8.1±0.4 days) anterior myocardial infarction. Electrolytic injury of the left circumflex coronary artery to induce thrombotic occlusion and posterolateral ischemia is initiated 1 h after the start of treatment[4]. Animal Model: Mongrel dogs of either sex, weighing 15-25 kg[3] Dosage: 0.1 mg/kg (followed by 0.02 mg/kg/h) Administration: i.v. for 5.5 hours Result: The pressor response was reduced by 87±4%.

[References]

[1]. Sachinidis A, et al. EXP3174, a metabolite of losartan (MK 954, DuP 753) is more potent than losartan in blockingthe angiotensin II-induced responses in vascular smooth muscle cells. J Hypertens. 1993 Feb;11(2):155-62.

[2]. Inada Y, et al. Binding of KRH-594, an antagonist of the angiotensin II type 1 receptor, to cloned human and rat angiotensin II receptors. Fundam Clin Pharmacol. 2002 Aug;16(4):317-23.

[3]. Richard V, et al. Comparison of the effects of EXP3174, an angiotensin II antagonist and enalaprilat on myocardial infarct size in anaesthetized dogs. Br J Pharmacol. 1993 Nov;110(3):969-74.

[4]. Lynch JJ Jr, et al. EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction. J Am Coll Cardiol. 1999 Sep;34(3):876-84.

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Boiling Point ]:
707.8±70.0 °C at 760 mmHg

[ Melting Point ]:
130-132ºC

[ Molecular Formula ]:
C22H21ClN6O2

[ Molecular Weight ]:
436.894

[ Flash Point ]:
381.8±35.7 °C

[ Exact Mass ]:
436.141449

[ PSA ]:
109.58000

[ LogP ]:
4.79

[ Vapour Pressure ]:
0.0±2.4 mmHg at 25°C

[ Index of Refraction ]:
1.695

[ Storage condition ]:
-20°C Freezer

Toxicological Information

CHEMICAL IDENTIFICATION

RTECS NUMBER :
NI4004850
CHEMICAL NAME :
1H-Imidazole-5-carboxylic acid, 2-butyl-4-chloro-1-((2'-(14-tetrazol-5-yl) (1,1'-biphenyl)-4-yl)methyl)-
CAS REGISTRY NUMBER :
124750-92-1
LAST UPDATED :
199712
DATA ITEMS CITED :
1
MOLECULAR FORMULA :
C22-H21-Cl-N6-O2
MOLECULAR WEIGHT :
436.94

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :
LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE :
Intraperitoneal
SPECIES OBSERVED :
Rodent - mouse
DOSE/DURATION :
441 mg/kg
TOXIC EFFECTS :
Sense Organs and Special Senses (Eye) - mydriasis (pupillary dilation) Behavioral - tremor Lungs, Thorax, or Respiration - respiratory depression
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 28,3959,1994

Safety Information

[ Safety Phrases ]:
24/25

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds

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