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The SARfaris: GPCR, Kinase, ADME

Tuesday, 21 June 2011

New Drug Approvals 2011 - Pt. XVIII Ezogabine (PotigaTM)

ATC code: N03AX21

On June 10th, FDA approved ezogabine (trade name Potiga, NDA 022345) to treat seizures associated with epilepsy in adults. However, before being launched, Potiga waits categorised by the Drug Enforcement Agency (for  review under the Controlled Substances Act) before formal marketing can proceed.

Epilepsy is a chronic neurological disorder involving a variety of symptoms caused by abnormal electrical activity in the brain. Episodic bouts ('seizures') can potentially be controlled by medication - however, for around 1 in 3 patients, this can not achieved satisfactorily with current medication. Ezogabine (ChEMBLID:41355) represents a novel approach, being the first anticonvulsant to specifically target neuronal potassium channels

The molecular targets of ezogabine are KCNQ/Kv7 potassium channels; by stabilizing their open conformation, the drug reduces their excitability. It shares its mode of action with the structurally very similar non-opioid analgesic Flupiritine (ChEMBLID:255044). There are numerous other anticonvulsant drugs approved, such as Carbamazepine (ChEMBLID:108), or Lamotrigine (ChEMBLID:741), two sodium channel blockers. 

Its name stem, -gab-, designates it a GABA mimetic (γ-Aminobutyric acid, ChEMBL ID 96, the predominant inhibitory neurotransmitter in the mammalian central nervous system). For a substance to be GABAergic, there is no need to directly compete with GABA, or to bind to the GABA receptor. However, there is evidence that ezogabine directly interacts with the GABAA receptor, acting as an allosteric agonist, synergetically increasing GABA binding, thereby excerting a sedative effect additionally to its primary target, KCNQ.

The main molecular target of ezogabine are the human KCNQ2 and -3 potassium channels (UniProt O43526 and O43525, respectively) - according to a patch clamp assay, it has 1.3 uM affinity for the murine KCNQ2 ortholog (see also ref). There are no experimental structures available for members of the KCNQ protein family, although there are X-Ray structures for other potassium channels.

Ezogabine (canonical smiles CCOC(=O)Nc1ccc(NCc2ccc(F)cc2)cc1N , standard InChI InChI=1S/C16H18FN3O2/c1-2-22-16(21)20-15-8-7-13(9-14(15)18)19-10-11-3-5-12(17)6-4-11/h3-9,19H,2,10,18H2,1H3,(H,20,21)) has 6 rotatable bonds, a molecular weight of 303.3 Da, 3 hydrogen bond donors, 2 hydrogen bond acceptors, and is thus fully Rule-of-Five compliant.

Ezogabin has moderately high bioavailability (50-60%), a high volume of distribution (6.2 L/kg) and a terminal half-life of 8 to 11 hours. Potiga tablets are administered three times daily. Ezogabine has a number of potentially severe adverse effects, such as urinary retention, and psychiatric symptoms such as new or intensification of depression, anxiety, psychosis, and in rare cases suicidal thoughts. 

Potiga has been developed by Valeant and will be marketed by GSK.

Full prescribing information will become available at launch of the drug.

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