Skip to main content

New Drug Approvals 2011 - Pt. XVI Telaprevir (IncivekTM)








ATC code (partial): J

On May 23rd, the FDA approved Telaprevir (Tradename: Incivek; Research Code: VX-950, NDA 201917), a Hepatitis C virus NS3 protease (HCV NS3) inhibitor, for the treatment of chronic hepatitis C virus genotype 1 infection, in combination with peginterferon alfa and ribavirin.

HCV is a prolonged infection that affects the liver and is caused by a small positive single-stranded RNA virus, which is transmitted by blood-to-blood contact. Chronic hepatitis C is normally asymptomatic, but may lead to liver fibrosis, and if untreated, potentially fatal liver failure. There is currently no vaccine for this type of hepatitis.

Telaprevir is an inhibitor of the hepatitis C virus (HCV) non-structural protein 3 (NS3) protease (ChEMBLID:CHEMBL4893; Uniprot ID:A3EZI9), a viral protein required for the proteolytic cleavage of the HCV encoded polyprotein (UniProt:P27958) into mature forms of the NS4A, NS4B, NS5A and NS5B proteins (NS3 is Uniprot: P27958[1027-1657]). These proteins are involved in the formation of the virus replication complex, and therefore are vital to its proliferation. In a biochemical assay, Telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM.

HCV NS3 is a serine protease (Pfam:PF02907). There are many protein structures known for this protein in complex with inhibitors, a typical entry is PDBe:3rc4, as expected from early genome annotation, the NS3 proteinase has a fold distantly related to the chymotrypsin-like family of serine proteinases, and contains the classic Asp-His-Ser catalytic triad.



The -vir USAN/INN stem covers antiviral agents, and the substem -previr indicates it is a serine protease inhibitor. Telaprevir is the second approved agent to target HCV NS3, following the approval earlier this month of Merck's Boceprevir (q.v.). Other compounds in this class in late stage clinical development/registration include Tibotec's TMC-435, and Bristol Myers Squibb's Asunaprevir (BMS-650032). Others at earlier stages of development include ABT-450, BI-201335, IDX-320, MK-5172, Vaniprevir (MK-7009), Narlaprevir (SCH-900518), Danoprevir (RG-7227, ITMN-191), BIT-225, VX-500, ACH-1625, GS-9256.



Telaprevir (IUPAC: (1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide; SMILES: CCCC(C(=O)C(=O)NC1CC1)NC(=O)C2C3CCCC3CN2C(=O)C(C(C)(C)C)NC(=O)C(C4CCCCC4)NC(=O)C5=NC=CN=C5; PubChem:3010818; ChEMBL ID: CHEMBL231813) has a molecular weight of 679.8 Da, contains 4 hydrogen bond donors, 8 hydrogen bond acceptors, and has an ALogP of 2.69. The inhibitor is clearly peptide like, containing four amino acid residues, mimicking the natural substrate of the protease, and including a 'warhead' - the alpha-keto amide, which covalently binds to the catalytic serine residue of the target enzyme.

Telaprevir is available as oral film-coated tablets of 375 mg. It has an apparent volume of distribution (Vd/F) of approximately 252 L, and, in patients who received a dose of 750 mg three times a day (the recommended daily dose is therefore a large 2.25 g (equivalent to 3,310 umol)), the exposure is characterised by an AUC of 22,300 ng.hr/mL, with a Cmax of 3510 ng/mL. Telaprevir should be administered with a standard fatty meal, since its bioavailability is enhanced by 237%. In vitro, protein plasma binding ranges from 59% to 76%.

The predominant metabolites of Telaprevir in plasma are the R-diastereoisomer (VRT-127394), which is approximately 30-fold less potent than the parent drug, pyrazinoic acid, and a metabolite that underwent reduction of the α-ketoamide bond of Telaprevir (which is, as expected not active against the target). Telaprevir is also metabolised by CYP3A4, being simultaneously a substrate and an inhibitor, and therefore, other therapeutic agents metabolised by CYP3A4 may prolong their therapeutic effect or adverse reactions. See prescribing information for the extensive list of drug-drug interactions and contraindications.

Following administration of a single oral dose of 750 mg, Telaprevir is eliminated with a mean plasma half-life (t1/2) of approximately 4.0 to 4.7 hours, and it has a mean total body clearance (CL/F) of approximately 32.4 L/hr.

Telaprevir was developed almost in parallel with Boceprevir, the first-in-class inhibitor of the HCV NS3 protease. Both drugs require a high daily dose for an effective response, and are generally similar with respect to their pharmacokinetic and pharmacokinetic parameters.

The license holder for Telaprevir is Vertex Pharmaceuticals Incorporated, and the full prescribing information can be found here. For more information, please visit the product website here.

Comments

Popular posts from this blog

ChEMBL 34 is out!

We are delighted to announce the release of ChEMBL 34, which includes a full update to drug and clinical candidate drug data. This version of the database, prepared on 28/03/2024 contains:         2,431,025 compounds (of which 2,409,270 have mol files)         3,106,257 compound records (non-unique compounds)         20,772,701 activities         1,644,390 assays         15,598 targets         89,892 documents Data can be downloaded from the ChEMBL FTP site:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/ Please see ChEMBL_34 release notes for full details of all changes in this release:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/chembl_34_release_notes.txt New Data Sources European Medicines Agency (src_id = 66): European Medicines Agency's data correspond to EMA drugs prior to 20 January 2023 (excluding vaccines). 71 out of the 882 newly added EMA drugs are only authorised by EMA, rather than from other regulatory bodies e.g.

New SureChEMBL announcement

(Generated with DALL-E 3 ∙ 30 October 2023 at 1:48 pm) We have some very exciting news to report: the new SureChEMBL is now available! Hooray! What is SureChEMBL, you may ask. Good question! In our portfolio of chemical biology services, alongside our established database of bioactivity data for drug-like molecules ChEMBL , our dictionary of annotated small molecule entities ChEBI , and our compound cross-referencing system UniChem , we also deliver a database of annotated patents! Almost 10 years ago , EMBL-EBI acquired the SureChem system of chemically annotated patents and made this freely accessible in the public domain as SureChEMBL. Since then, our team has continued to maintain and deliver SureChEMBL. However, this has become increasingly challenging due to the complexities of the underlying codebase. We were awarded a Wellcome Trust grant in 2021 to completely overhaul SureChEMBL, with a new UI, backend infrastructure, and new f

Accessing SureChEMBL data in bulk

It is the peak of the summer (at least in this hemisphere) and many of our readers/users will be on holiday, perhaps on an island enjoying the sea. Luckily, for the rest of us there is still the 'sea' of SureChEMBL data that awaits to be enjoyed and explored for hidden 'treasures' (let me know if I pushed this analogy too far). See here and  here for a reminder of SureChEMBL is and what it does.  This wealth of (big) data can be accessed via the SureChEMBL interface , where users can submit quite sophisticated and granular queries by combining: i) Lucene fields against full-text and bibliographic metadata and ii) advanced structure query features against the annotated compound corpus. Examples of such queries will be the topic of a future post. Once the search results are back, users can browse through and export the chemistry from the patent(s) of interest. In addition to this functionality, we've been receiving user requests for  local (behind the