Ambrisentan

Base Information

• Chemical Name: Ambrisentan
• CAS No.: 177036-94-1
• Molecular Formula: C₂₂H₂₂N₂O₄
• Molecular Weight: 378.428
• Hs Code.: 29335990
• European Community (EC) Number: 658-059-9
• UNII: HW6NV07QEC
• DSSTox Substance ID: DTXSID4046282
• Nikkaji Number: J2.651.033C
• Wikipedia: Ambrisentan
• Wikidata: Q410789
• NCI Thesaurus Code: C72694
• RXCUI: 358274
• Pharos Ligand ID: TQB2ZLQZX2Y3
• Metabolomics Workbench ID: 149762
• ChEMBL ID: CHEMBL1111
• Mol file: 177036-94-1.mol

Synonyms:(+)-(2S)-2-((4,6-dimethylpyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenylpropanoic acid;(+)-ambrisentan;(+-)-ambrisentan;(-)-ambrisentan;(R)-ambrisentan;(S)-ambrisentan;ambrisentan;ambrisentan, (+-)-;ambrisentan, (-)-;ambrisentan, (R)-;BSF 208075;BSF-208075;BSF208075;GSK 1325760;GSK 1325760A;GSK-1325760;GSK-1325760A;GSK1325760;GSK1325760A;Letairis;LU 208075;LU-208075;LU208075;Volibris

Chemical Property of Ambrisentan

Chemical Property:

• Vapor Pressure: 5.56E-13mmHg at 25°C
• Melting Point: >150°C (dec.)
• Refractive Index: 1.593
• Boiling Point: 551.1 °C at 760 mmHg
• PKA: 0.97±0.10(Predicted)
• Flash Point: 287.1 °C
• PSA: 81.54000
• Density: 1.228 g/cm³
• LogP: 3.51560
• Storage Temp.: -20°C Freezer
• Solubility.: DMSO (Slightly), Methanol (Slightly)
• XLogP3: 3.8
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 6
• Rotatable Bond Count: 7
• Exact Mass: 378.15795719
• Heavy Atom Count: 28
• Complexity: 475

Purity/Quality:

99%, ^*data from raw suppliers

Ambrisentan ^*data from reagent suppliers

Safty Information:

• Statements: 62/63
• Safety Statements: 53-36/37/39-45

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Pulmonary Arterial Hypertension Agents
• Canonical SMILES: CC1=CC(=NC(=N1)OC(C(=O)O)C(C2=CC=CC=C2)(C3=CC=CC=C3)OC)C
• Isomeric SMILES: CC1=CC(=NC(=N1)O[C@H](C(=O)O)C(C2=CC=CC=C2)(C3=CC=CC=C3)OC)C
• Recent ClinicalTrials: mulTi-Arm Therapeutic Study in Pre-ICu Patients Admitted With Covid-19 - Experimental Drugs and Mechanisms
• Recent EU Clinical Trials: A randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ambrisentan in patients with severe COVID-19
• Recent NIPH Clinical Trials: Drug interactions and effects of combination therapy for pulmonary arterial hypertension
• 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. 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.
• Uses: Nonpeptide endothelin ETA receptor antagonist. Antihypertensive antihypertensive;endothelin receptor antagonist
• Clinical Use: Endothelin A (ETA) receptor antagonist: Treatment of pulmonary arterial hypertension
• 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.

Technology Process of Ambrisentan

There total 40 articles about Ambrisentan which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 96.0%

(S)-methyl-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate (1240470-84-1) → 4,6-dimethyl-2(1H)-pyrimidinone (108-79-2) + ambrisentan (177036-94-1)

Guidance literature:

With potassium hydroxide; In 1,4-dioxane; water; at 80 ℃; for 4h; Reagent/catalyst; Solvent; Inert atmosphere;

DOI:10.1021/acs.oprd.8b00184

Reference yield: 95.0%

4,6-dimethyl-2-methylsulfonylpyrimidine (35144-22-0) + (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (178306-52-0,178306-49-5) → ambrisentan (177036-94-1)

Guidance literature:

(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid; With sodium hydride; In N,N-dimethyl-formamide; at 20 ℃; for 2.5h; Inert atmosphere;

4,6-dimethyl-2-methylsulfonylpyrimidine; In N,N-dimethyl-formamide; at 20 ℃; for 16h; Inert atmosphere;

Reference yield: 90.9%

(S)-1-(3-methoxyphenyl)ethylammonium (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate (1260633-84-8) + 4,6-dimethyl-2-methylsulfonylpyrimidine (35144-22-0) → ambrisentan (177036-94-1)

Guidance literature:

With sodium t-butanolate; In N,N-dimethyl-formamide; at 20 - 30 ℃; for 3h; Product distribution / selectivity;

upstream raw materials:

(S)-methyl-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate

benzophenone

3,3-diphenyloxirane-2-carboxylic acid methyl ester

2-hydroxy-3-methoxy-3,3-diphenylpropionicacid methyl ester

Downstream raw materials:

(S)-1-phenylethan-1-aminium (S)-2-((4,6-dimethyl-pyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenylpropanoate

ambrisentan

(S)-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid

Refernces

• 1、 -. "An improved method of preparing Anritsu tezosentan". Paragraph 0044; 0045; 0046; 0047; 0048; 0049; 0050. . Retrieved 2019/05/04.
• 2、 Feng, Wei-Dong,Zhuo, Song-Ming,Yu, Jun,Zhao, Chuan-Meng,Zhang, Fu-Li. "Process Research for (+)-Ambrisentan, an Endothelin-A Receptor Antagonist". . p. 1200 - 1207. Retrieved 2018/09/06.