177036-94-1

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 ofET_A and ET_B receptors.

White to Off White Solid

Abbott (US)

antihypertensive;endothelin receptor antagonist

Nonpeptide endothelin ETA receptor antagonist. Antihypertensive

ChEBI: Ambrisentan is a diarylmethane.

Letairis

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.

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

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.

This orally active endothelin receptor antagonist (FW = 378.42 g/mol; CAS 177036-94-1), also known by its code names LU-208075, BSF-208075, its trade names Letairis? and Volibris?, and by its IUPAC name (2S) -2- [ (4,6-dimethylpyrimidin-2-yl) oxy]-3-methoxy-3,3-diphenylpropanoic acid, is a FDA-approved, once-daily drug for treating pulmonary hypertension. Because endothelin constricts blood vessels and elevates blood pressure, endothelin receptor antagonists (ETRAs) prevent constriction/narrowing of blood vessels, thereby enhancing blood flow. There are no known interactions between ambrisentan and cytochrome P450 isoenzymes (metabolism, induction or inhibition) that might alter the activity of P450- metabolized drugs. Key Pharmacokinetic Parameters: See Appendix II in Goodman & Gilman’s THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 12th Edition (Brunton, Chabner & Knollmann, eds.) McGraw-Hill Medical, New York.

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

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.

Store at +4°C

[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.