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Details

Stereochemistry ABSOLUTE
Molecular Formula C22H22N2O4
Molecular Weight 378.4211
Optical Activity ( + )
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of AMBRISENTAN

SMILES

COC([C@H](OC1=NC(C)=CC(C)=N1)C(O)=O)(C2=CC=CC=C2)C3=CC=CC=C3

InChI

InChIKey=OUJTZYPIHDYQMC-LJQANCHMSA-N
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)/t19-/m1/s1

HIDE SMILES / InChI

Description

Ambrisentan (alternative Names: BSF 208075; GSK 1325760; GSK1325760A; Letairis) is an endothelin receptor antagonist that is selective for the endothelin type-A (ETA) receptor. The chemical name of ambrisentan is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. Ambrisentan is indicated for the treatment of pulmonary arterial hypertension. It is approved in Europe, Canada and the United States for use as a single agent to improve exercise ability and delay clinical worsening. In addition, it is approved in the United States for use in combination with tadalafil to reduce the risks of disease progression, hospitalization and to improve exercise ability. As an endothelin receptor antagonist, ambrisentan prevents endogenous endothelin peptide from constricting the muscles in blood vessels, allowing them to relax and permit a reduction in blood pressure. Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance. In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH. Ambrisentan is a high-affinity (Ki=0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor (>4000-fold). The clinical impact of high selectivity for ETA is not known.

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
0.011 nM [Ki]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
LETAIRIS

Cmax

ValueDoseCo-administeredAnalytePopulation
838.3 ng/mL
10 mg single, oral
AMBRISENTAN plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
6976.5 ng × h/mL
10 mg single, oral
AMBRISENTAN plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
18.9 h
10 mg single, oral
AMBRISENTAN plasma
Homo sapiens
9 h
steady-state, oral
AMBRISENTAN plasma
Homo sapiens

Doses

AEs

Drug as perpetrator​

Drug as victim

PubMed

Sample Use Guides

In Vivo Use Guide
5 mg once daily, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated. Tablets may be administered with or without food.
Route of Administration: Oral
In Vitro Use Guide
The effect of the novel and ET(A) receptor selective antagonist LU 208075 (AMBRISENTAN) was characterized by the contraction and relaxation induced by ET-1 and bigET-1 on rat basilar artery. Concentration-effect curves were constructed by cumulative application of ET-1 or bigET-1 in the presence of LU 208075 (10(-7)M, 10(-6)M, and 10(-5)M). The effect of LU 208075 was determined by the pA(2) value. The contraction by ET-1 and bigET-1 was inhibited by LU 208075 in a dose-dependent manner.