Chronic obstructive pulmonary disease (COPD) is characterised by the occurrence of
chronic bronchitis or
emphysema, a pair of commonly co-existing diseases of the lungs in which the airways become narrowed. Bronchial spasms, a sudden constriction of the muscles in the walls of the
bronchioles, occur frequently in COPD.
Vilanterol is a new long-acting beta2 receptor agonist that through the activation of the beta2 adrenergic receptors present in the bronchial smooth muscle, leads to bronchodilation, and consequently eases the symptoms of COPD.
The beta
2 adrenergeic receptor (Uniprot:
P07550; ChEMBL:
CHEMBL210) belongs to the G-protein coupled receptor (GPCR) type 1 family, and binds the endogenous neurotransmitter
adrenaline. Since it is coupled to a Gs protein, its activation leads ultimately to an increase in
cyclic AMP (cAMP), which cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
>ADRB2_HUMAN Beta-2 adrenergic receptor
MGQPGNGSAFLLAPNGSHAPDHDVTQERDEVWVVGMGIVMSLIVLAIVFGNVLVITAIAK
FERLQTVTNYFITSLACADLVMGLAVVPFGAAHILMKMWTFGNFWCEFWTSIDVLCVTAS
IETLCVIAVDRYFAITSPFKYQSLLTKNKARVIILMVWIVSGLTSFLPIQMHWYRATHQE
AINCYANETCCDFFTNQAYAIASSIVSFYVPLVIMVFVYSRVFQEAKRQLQKIDKSEGRF
HVQNLSQVEQDGRTGHGLRRSSKFCLKEHKALKTLGIIMGTFTLCWLPFFIVNIVHVIQD
NLIRKEVYILLNWIGYVNSGFNPLIYCRSPDFRIAFQELLCLRRSSLKAYGNGYSSNGNT
GEQSGYHVEQEKENKLLCEDLPGTEDFVGHQGTVPSDNIDSQGRNCSTNDSLL
There are 11 resolved 3D structures for this protein with vary degrees of resolution (2.40 to 3.50 Å) and different fusion protocols. For instance,
3ny8, is a fused protein of the human beta
2 adrenergeic receptor with Lysozyme Bacteriophage T4, with a resolution of 2.84 Å and an inverse agonist bound to it (
ICI-118,551, ChEMBL:
CHEMBL513389):
The full list of PDBe entries can be found
here.
Vilanterol (IUPAC Name: 4-[(1R)-2-[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol; Canonical smiles: OCc1cc(ccc1O)[C@@H](O)CNCCCCCCOCCOCc2c(Cl)cccc2Cl; ChEMBL:
CHEMBL1198857; PubChem:
10184665; ChemSpider:
8360167; Standard InChI Key: DAFYYTQWSAWIGS-DEOSSOPVSA-N) is a synthetic small molecule, with a molecular weight of 486.4 Da, 6 hydrogen bond acceptors, 4 hydrogen bond donors, and has an ALogP of 4.22. The compound is therefore fully compliant with the rule of five.
Breo Ellipta is available as a dry powder inhaler and the recommended daily dose is one inhalation of fluticasone furoate/vilanterol 100/25 mcg. Following inhalation, vilanterol peak plasma concentrations are reached within 10 minutes, and its absolute bioavailability is 27.3%. At steady state, following intravenous administration, the mean volume of distribution of vilanterol (Vd/F) was 165L in healthy subjects. Vilanterol is strongly bound to human plasma proteins (93.3 %).
Vilanterol is primarily metabolized in the liver by CYP3A4. Therefore, concomitant administration of potent CYP3A4 inhibitors should be avoided. Vilanterol metabolites are primarily excreted in urine (70%) and feces (30%). The effective half-life (t1/2) for Vilanterol is approximately 21 hours in patients with COPD.
Breo Ellipta has been issued with a black box warning due to Vilanterol increased risk of asthma-related death, a known risk to all long-acting beta2-adrenergic agonists.
The license holder for Breo Ellipta
TM is
GlaxoSmithKline, and the full prescribing information can be found
here.