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The SARfaris: GPCR, Kinase, ADME

Wednesday, 6 July 2011

New Drug Approvals 2011 - Pt. XXII Indacaterol Maleate (ArcaptaTM)

ATC Code: R03AC18

On July 1, the FDA approved indacaterol maleate (NDA 022383) for the long-term treatment of patients with chronic obstructive pulmonary disease (COPD) a chronic and serious disease involving restriction of full lung function. The narrowing of airways of COPD is irreversible, and follows inflammation in the lung, believed to be linked to environmental pollutants such as tobacco smoke, workplace dusts and urban air pollution. Indacaterol maleate is administered as an aerosol through a dry powder inhaler and carries a boxed warning for asthma-related death and is not indicated for the treatment of asthma.

The active ingredient of indacaterol maleate is indacaterol (ChEMBL: 1095777) an agonist of the beta-2 adrenergic receptor (Uniprot: P07550, ChEMBL: 210) with measured EC50 of 11nM. Indacaterol exerts its effect through activation of the beta-2 adrenergic receptor, leading to smooth muscle relaxation and a widening of bronchioli in the lungs. Activation of the beta-2 adrenergic receptor stimulates the intracellular adenyl cyclase and increases cAMP levels, which in turn leads to a reduction of the level of calcium ions inside smooth muscle cells. Other long acting beta-adrenoceptor agonists (LABA) such as salmeterol, formoterol and bambuterol entered the market during the 1980s. The duration of action of these earlier compounds is 12 hours, while for indacaterol it is 24 hours.

Multiple crystal structures of the beta-2 adrenergic receptor now exist (PDBe: 2R4R, 2R4S, 2RH1, 3D4S, 3KJ6, 3NY8, 3NY9, 3NYA, 3P0G, 3PDS), a nano-body stabilized structure of the receptor in its activated form is shown below (PDBe: 3p0g).

Indacaterol (IUPAC: (R)-5-(2-((5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino)-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, SMILES: CCc1cc2CC(Cc2cc1CC)NC[C@H](O)c3ccc(O)c4NC(=O)C=Cc34 , InChI: 1S/C24H28N2O3/c1-3-14-9-16-11-18(12-17(16)10-15(14)4-2)25-13-22(28)19-5-7-21(27)24-20(19)6-8-23(29)26-24/h5-10,18,22,25,27-28H,3-4,11-13H2,1-2H3,(H,26,29)/t22-/m0/s1, ChemSpider: 5293751, ChEMBL: 1095777) is a is a synthetic small molecule drug with one chiral center. It has a molecular weight of 392.5 Da and calculated LogP of 3.93. Indacaterol has 4 hydrogen bond acceptors and 4 hydrogen bond donors and therefore fully complies with Lipinski's rule of five. The picture below shows both the active ingredient, indacaterol, and maleate.

The USAN stem name -terol indicates that indacaterol is a phenethylamine derivative bronchodilator. Other -terols include salmeterol, formoterol, bambuterol, vilanterol, milveterol and levalbuterol.

Indacaterol's bioavailability after inhalation is (at the recommended dose range of 75-150 µg) is 43-45% and the volume of distribution (Vd) is between 2.36 and 2.56 and a clearance (CL) of about Steady-state of Indacaterol levels is reached within 12 to 15 days. Plasma protein binding (ppb) of the dosed drug is 95.1-96.2%. Excretion of indacaterol is mainly through the fecal route, either as the parent compound (54% of the dose) or hydroxylated metabolite (23% of the dose).

Indacaterol maleate is administered once daily as an aerosol containing  75-150 µg of active ingredient from a powder inhaler.

The full prescribing information can be found here.

Indacaterol maleate was approved by the European commission in 2009 and is marketed in Europe as Onbrez. In the US, indacaterol maleate will be marketed by Novartis under the trade name Arcapta. 

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