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The SARfaris: GPCR, Kinase, ADME

Sunday, 26 May 2013

New Drug Approvals 2013 - Pt. VIII - Fluticasone furoate and Vilanterol (Breo ElliptaTM)

ATC Code: R03AK10
Wikipedia: Vilanterol

On May 10th, the FDA approved Vilanterol (Tradename: Breo Ellipta; Research Code: GW-642444M), a long-acting beta2-adrenergic agonist, in combination with the already approved fluticasone furoate, an inhaled corticosteroid, for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).

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 beta2 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

There are 11 resolved 3D structures for this protein with vary degrees of resolution (2.40 to 3.50 &#197) and different fusion protocols. For instance, 3ny8, is a fused protein of the human beta2 adrenergeic receptor with Lysozyme Bacteriophage T4, with a resolution of 2.84 &#197 and an inverse agonist bound to it (ICI-118,551, ChEMBL: CHEMBL513389):

The full list of PDBe entries can be found here.

The -terol USAN/INN stem covers bronchodilators structurally related with phenethylamine. Members of these class include for example Salmeterol (ChEMBL: CHEMBL1263), Formoterol (ChEMBL: CHEMBL1256786) and Indacaterol (ChEMBL: CHEMBL1095777), all long-acting beta2-adrenergic agonists also approved for the management of COPD. For a full list of compounds check ChEMBL.

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 ElliptaTM is GlaxoSmithKline, and the full prescribing information can be found here.

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