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The SARfaris: GPCR, Kinase, ADME

Tuesday, 24 May 2011

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, 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.

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