Skip to main content

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.


Popular posts from this blog

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

ChEMBL 29 Released

  We are pleased to announce the release of ChEMBL 29. This version of the database, prepared on 01/07/2021 contains: 2,703,543 compound records 2,105,464 compounds (of which 2,084,724 have mol files) 18,635,916 activities 1,383,553 assays 14,554 targets 81,544 documents Data can be downloaded from the ChEMBL FTP site: .  Please see ChEMBL_29 release notes for full details of all changes in this release: New Deposited Datasets EUbOPEN Chemogenomic Library (src_id = 55, ChEMBL Document IDs CHEMBL4649982-CHEMBL4649998): The EUbOPEN consortium is an Innovative Medicines Initiative (IMI) funded project to enable and unlock biology in the open. The aims of the project are to assemble an open access chemogenomic library comprising about 5,000 well annotated compounds covering roughly 1,000 different proteins, to synthesiz

Identifying relevant compounds in patents

  As you may know, patents can be inherently noisy documents which can make it challenging to extract drug discovery information from them, such as the key targets or compounds being claimed. There are many reasons for this, ranging from deliberate obfuscation through to the long and detailed nature of the documents. For example, a typical small molecule patent may contain extensive background information relating to the target biology and disease area, chemical synthesis information, biological assay protocols and pharmacological measurements (which may refer to endogenous substances, existing therapies, reaction intermediates, reagents and reference compounds), in addition to description of the claimed compounds themselves.  The SureChEMBL system extracts this chemical information from patent documents through recognition of chemical names, conversion of images and extraction of attached files, and allows patents to be searched for chemical structures of interest. However, the curren

Julia meets RDKit

Julia is a young programming language that is getting some traction in the scientific community. It is a dynamically typed, memory safe and high performance JIT compiled language that was designed to replace languages such as Matlab, R and Python. We've been keeping an an eye on it for a while but we were missing something... yes, RDKit! Fortunately, Greg very recently added the MinimalLib CFFI interface to the RDKit repertoire. This is nothing else than a C API that makes it very easy to call RDKit from almost any programming language. More information about the MinimalLib is available directly from the source . The existence of this MinimalLib CFFI interface meant that we no longer had an excuse to not give it a go! First, we added a BinaryBuilder recipe for building RDKit's MinimalLib into Julia's Yggdrasil repository (thanks Mosè for reviewing!). The recipe builds and automatically uploads the library to Julia's general package registry. The build currently targe

New Drug Warnings Browser

As mentioned in the announcement post of  ChEMBL 29 , a new Drug Warnings Browser has been created. This is an updated version of the entity browsers in ChEMBL ( Compounds , Targets , Activities , etc). It contains new features that will be tried out with the Drug Warnings and will be applied to the other entities gradually. The new features of the Drug Warnings Browser are described below. More visible buttons to link to other entities This functionality is already available in the old entity browsers, but the button to use it is not easily recognised. In the new version, the buttons are more visible. By using those buttons, users can see the related activities, compounds, drugs, mechanisms of action and drug indications to the drug warnings selected. The page will take users to the corresponding entity browser with the items related to the ones selected, or to all the items in the dataset if the user didn’t select any. Additionally, the process of creating the join query is no