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Ambrisentan

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Ambrisentan Basic information

Product Name:
Ambrisentan
Synonyms:
  • BSF 208075,(+)-(2S)-2-[(4,6-DIMETHYLPYRIMIDIN-2-YL)OXY]-3-METHOXY-3,3-DIPHENYLPROPANOIC ACID
  • AMBRISENTAN
  • (aS)-a-[(4,6-Dimethyl-2-pyrimidinyl)oxy]--methoxy--phenylbenzenepropanoic Acid
  • BSF 208075
  • LU 208075
  • 2-(4,6-Dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-di(phenyl)propanoic acid
  • (S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropanoic acid
  • (+-)-(2S)-2-((4,6-Dimethylpyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenylpropanoic acid,bsf-208075
CAS:
177036-94-1
MF:
C22H22N2O4
MW:
378.42
EINECS:
658-059-9
Product Categories:
  • APIs
  • Aromatics
  • Heterocycles
  • Intermediates & Fine Chemicals
  • Pharmaceuticals
  • Other APIs
Mol File:
177036-94-1.mol
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Ambrisentan Chemical Properties

Melting point:
>150°C (dec.)
Boiling point:
551.1±60.0 °C(Predicted)
Density 
1.228±0.06 g/cm3(Predicted)
storage temp. 
Sealed in dry,2-8°C
solubility 
DMSO (Slightly), Methanol (Slightly)
form 
Solid
pka
0.97±0.10(Predicted)
color 
White to Off-White
Merck 
14,384
InChI
InChI=1S/C22H22N2O4/c1-15-14-16(2)24-21(23-15)28-19(20(25)26)22(27-3,17-10-6-4-7-11-17)18-12-8-5-9-13-18/h4-14,19H,1-3H3,(H,25,26)
InChIKey
OUJTZYPIHDYQMC-UHFFFAOYSA-N
SMILES
C(OC1N=C(C)C=C(C)N=1)(C(O)=O)C(OC)(C1=CC=CC=C1)C1=CC=CC=C1
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Safety Information

Risk Statements 
62/63
Safety Statements 
53-36/37/39-45
RTECS 
UA2459660
HS Code 
29335990
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Ambrisentan Usage And Synthesis

Description

Ambrisentan is a selective endothelin-A (ETA) receptor antagonist introduced for the oral treatment of patients with pulmonary arterial hypertension (PAH), to improve exercise capacity and delay clinical worsening. It is the third ET-receptor antagonist to be marketed for this indication behind bosentan and sitaxsentan. PAH is a rare disease of the small pulmonary arteries characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, and ultimately, right ventricular failure and premature death. Early symptoms of PAH include gradual onset of shortness of breath, fatigue, palpitation, edema, and fainting. Endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen, is a key contributor to the acceleration of the disease, and its effects are mediated through activation ofETA and ETB receptors.

Description

Ambrisentan is a nonpeptide endothelin A (ETA) receptor antagonist (IC50s = 0.251, 0.316, 0.398, 251, and 630 nM for rat preparations of heart, bladder, kidney, lung, and cerebral cortex, respectively). It inhibits contraction of isolated rabbit aortic rings induced by endothelin-1 (ET-1; ) by 43.23% when used at a concentration of 1 μM. Ambrisentan inhibits ET-1-induced contraction of human pulmonary and radial arteries in vitro (Kd = 0.042 and 0.11 μM, respectively). In a rat model of neonatal hyperoxic lung injury, ambrisentan (20 mg/kg per day, s.c.) reduces pulmonary arterial hypertension (PAH) as well as decreases PAH-induced right ventricular hypertrophy (RVH) and peak RV pressure. Formulations containing ambrisentan have been used to treat PAH.

Chemical Properties

White to Off White Solid

Originator

Abbott (US)

Uses

Nonpeptide endothelin ETA receptor antagonist. Antihypertensive

Uses

antihypertensive;endothelin receptor antagonist

Definition

ChEBI: Ambrisentan is a diarylmethane.

brand name

Letairis

General Description

Ambrisentan, (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid(Letairis), is a potent ETA selective endothelin antagonist that,is indicated, in the treatment of pulmonary arterial hypertension(PAH). PAH is a rare disease that if left untreated has ahigh mortality rate. In June of 2007, the FDA granted approvalof ambrisentan for once-daily treatment of PAH.Studies have shown that it improves a 6-minute walk by about30 to 60 m for patients receiving placebo.

Clinical Use

Endothelin A (ETA) receptor antagonist:
Treatment of pulmonary arterial hypertension

Synthesis

Both the discovery and process routes to the synthesis of ambrisentan have been published and the process route is described as shown in the scheme. Reacting a mixture of benzophenone (14) and sodium methoxide in THF at 0??C with methylchloroacetate over a four hour period provided glycidate 15 which was taken forward without purification to the subsequent step. Addition of ptoluenesulfonic acid monohydrate to a solution of glycidate 15 in methanol was followed by heating at reflux and distilling out the solvent until the temperature reached 66??C. While the solution was still refluxing, 10% potassium hydroxide was added and the remaining organic solvent was distilled out until the temperature reached 94??C, providing complete hydrolysis to acid 16. The reaction was cooled to room temperature and diluted with water and methyl tert-butylether (MTBE) then acidified with 10% sulfuric acid. The MTBE layer was separated and taken to the next step. Additional MTBE and methanol were added to the crude acid 17 and the resulting mixture was heated at reflux. (S)-1-(4-chlorophenyl) ethylamine was added to the refluxing solution and the resulting mixture was allowed to cool to 0-5??C slowly at a rate of 10??C/h which resulted in crystallization of the salt 19 in 33% overall yield from benzophenone and 99% e.e. The chiral hydroxyl acid salt 19 was mixed with sulfone 20 and lithium amide in a toluene/DMF mixture and heated at 45??C for 12 hours to give, after acidic workup and crystallization, ambrisentan (II) in 84% yield as a colorless powder with 99.8% e.e.

Drug interactions

Potentially hazardous interactions with other drugs
Ciclosporin: concentration of ambrisentan doubled with an increased risk of side effects; maximum dose 5 mg daily.

Metabolism

Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S) to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan (which has little activity) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide.
Ambrisentan is excreted mainly by the liver, although the contribution of hepatic metabolism and biliary excretion is unknown.

storage

Store at +4°C

References

[1] vatter h, seifert v. ambrisentan, a non-peptide endothelin receptor antagonist. cardiovascular drug reviews, 2006, 24(1): 63-76.
[2] barst r j. a review of pulmonary arterial hypertension: role of ambrisentan. vascular health and risk management, 2007, 3(1): 11.

AmbrisentanSupplier

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