177036-94-1 Usage
Description
Ambrisentan, also known as (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid (Letairis), is a potent and selective endothelin-A (ETA) receptor antagonist. It is primarily used for the oral treatment of patients with pulmonary arterial hypertension (PAH), aiming to improve exercise capacity and delay clinical worsening. Ambrisentan is a white to off-white solid and was the third ET-receptor antagonist to be marketed for PAH treatment, following bosentan and sitaxsentan.
Uses
Used in Pharmaceutical Industry:
Ambrisentan is used as an antihypertensive agent for the treatment of pulmonary arterial hypertension (PAH). It works by blocking the ETA receptors, reducing the effects of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that contributes to the acceleration of PAH.
Ambrisentan is used as an endothelin receptor antagonist to improve exercise capacity and delay clinical worsening in patients with PAH. By inhibiting the ETA receptors, it helps to reduce pulmonary vascular resistance and pulmonary arterial pressure, thus preventing right ventricular failure and premature death associated with PAH.
In addition to its primary use in treating PAH, Ambrisentan has shown potential in reducing pulmonary arterial hypertension and PAH-induced right ventricular hypertrophy (RVH) in a rat model of neonatal hyperoxic lung injury. This suggests that Ambrisentan may have broader applications in the treatment of various lung-related conditions.
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.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 177036-94-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,7,7,0,3 and 6 respectively; the second part has 2 digits, 9 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 177036-94:
(8*1)+(7*7)+(6*7)+(5*0)+(4*3)+(3*6)+(2*9)+(1*4)=151
151 % 10 = 1
So 177036-94-1 is a valid CAS Registry Number.
InChI:InChI=1/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)/t19-/m1/s1
177036-94-1Relevant articles and documents
Enantioselective epoxidation by the chiral auxiliary approach: Asymmetric total synthesis of (+)-Ambrisentan
Madhu, Madasu,Doda, Sai Reddy,Begari, Prem Kumar,Dasari, Krishna Rao,Thalari, Gangadhar,Kadari, Sudhakar,Yadav, Jhillu Singh
, p. 942 - 946 (2021/02/26)
Enantioselective and a highly concise total synthesis of Ambrisentan are described. The chiral auxiliary controlled enantioselective epoxidation (Azerad protocol), photochemical regioselective epoxide opening, and base mediated ester hydrolysis reactions
Preparation method of ambrisentan
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Paragraph 0056-0064, (2019/05/15)
The invention belongs to the field of medicine synthesis and particularly relates to a preparation method of ambrisentan, wherein the ambrisentan is prepared through a benzyl protection reaction, a condensation reaction, and a benzyl protection group removal reaction in the method. A benzyl-protected intermediate is delivered to the next step of the condensation reaction without post-treatment. The debenzylation reaction is carried out through catalytic hydrogenation, which is green and environment-friendly and is simple in reaction operations and post-treatment. A reaction liquid is treated and pulped in an ether solvent, so that residual raw materials and intermediate in the solid are removed effectively. When an ambrisentan crude product is prepared, a recrystallization step with a methanol/water mixed solvent is carried out to obtain high-purity ambrisentan. The method is fewer in steps and high in yield, has short production cycle, simple operation, good reproducibility and mild conditions, and is suitable for industrial production.
