ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Friday, 27 July 2012

New Drug Approvals 2012 - Pt. XVI - Aclidinium bromide (TudorzaTM PressairTM)

ATC Code: R03BB05
Wikipedia: Aclidinium bromide

On July 23th, the FDA approved Aclidinum bromide (Tradename: Tudorza PressairTM; Research Codes: LAS-34273, LAS W-330), a muscarinic acetylcholine M3 receptor antagonist, 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.

Aclidinum bromide is a long-acting antimuscarinic agent that through the inhibition of the muscarinic acetylcholine M3 receptors present in the airway smooth muscle, leads to bronchodilation, and consequently eases the symptoms of COPD.

The muscarinic acetylcholine M3 receptor (Uniprot: P20309, ChEMBL: CHEMBL245) belongs to the G-protein coupled receptor (GPCR) type 1 family, and binds the endogenous neurotransmitter acethylcoline. Since it is coupled to a Gq protein, its inhibition leads to a decrease of intracellular calcium levels, and consequently smooth muscle relaxation.

>ACM3_HUMAN Muscarinic acetylcholine receptor M3

There is one partially resolved 3D structure for this protein (2CSA), but there are now several relevant homologous structures of other closely related members of the family (see here for a current list of rhodopsin-like GPCR structures).

The -ium USAN/INN stem covers quaternary ammonium compounds. Members of these class include for example tiotropium bromide (ChEMBL ID: CHEMBL1182657), and ipratropium bromide (ChEMBL ID: CHEMBL1615433, which are also anthicholinergic drugs approved for the treatment of COPD.

Aclidinum bromide (IUPAC: [1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-3-yl]2-hydroxy-2,2-dithiophen-2-ylacetate bromide; Canonical smiles (for active quaternary amine): OC(C(=O)O[C@H]1C[N+]2(CCCOc3ccccc3)CCC1CC2)(c4cccs4)c5cccs5 ; PubChem: 11467166; Chemspider: 9609381; ChEMBLID: CHEMBL1194325; Standard InChI Key: ASMXXROZKSBQIH-VITNCHFBSA-N) is a synthetic quaternary ammonium compound with one chiral center, a molecular weight of 484.7 Da, 7 hydrogen bond acceptors, 1 hydrogen bond donor, and has an ALogP of 3.4. The compound is therefore fully rule-of-five compliant.

Aclidinum bromide is available as a dry powder inhaler and the recommended daily dose is two oral inhalations of 400 mcg. It has an apparent volume of distribution of 300 L following intravenous administration of 400 mcg, and its absolute bioavailability is approximately 6%. The estimated effective half-life of Aclidinum (t1/2) is 5 to 8 hours.

The major route of metabolism for aclidinum bromide is non-enzymatic and esterases-mediated hydrolysis, being rapidly and extensively converted to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors - this leads to very low systemic exposure of the active aclidinium species. Excretion of aclidinium bromide is mainly through the urine (54 - 65%) and faeces (20 - 30%), where only 1% is excreted as unchanged aclidinium. The total clearance is approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers.

The license holder for TudorzaTM PressairTM is Forest Pharmaceuticals, and the full prescribing information can be found here.

1 comment:

Andrew said...

In addition to the structure of the peptide mentioned in the post, there's also a recent structure of the M3 receptor in complex with the drug tiotropium. The PDB ID is 4DAJ, and Pubmed ID for the associated publication is 22358844.