ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Tuesday, 17 May 2011

New Drug Approvals 2011 - Pt. XIV Boceprevir (VictrelisTM)

ATC code (partial): J

On May 13th, the FDA approved Boceprevir (Tradename: Victrelis; Research Code: SCH-503034, NDA202258), 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.

Chronic hepatitis C genotype 1 is a prolonged infection that affects the liver and is caused by a small 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 thus liver failure.

Boceprevir is a first-in-class 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 survival. HCV NS3 is a serine proteinase (Pfam:PF02907). Through a reactive center, the (alpha)-ketoamide functional group, boceprevir binds covalently to a serine in the active site of NS3 protease (S139), inhibiting viral replication in HCV-infected host cells. In a biochemical assay, Boceprevir inhibited the activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes, with Ki values of 14 nM for each subtype.

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. Boceprevir is the first approved agent to target HCV NS3. Other compounds in this class in late stage clinical development/registration include Vertex's Telaprevir (VX-950, Incivek), 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), Narlaprivir (SCH-900518), Danoprevir (RG-7227, ITMN-191), BIT-225, VX-500, ACH-1625, GS-9256, .

Boceprevir (IUPAC: (1S,4S,5R)-N-(4-amino-1-cyclobutyl-3, 4-dioxobutan 2-yl)-3-[(2S)-2-(tert-butylcarbamoylamino)-3, 3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-4-carboxamide; SMILES: CC1(C2C1C(N(C2)C(=O)C(C(C)(C)C)NC(=O)NC(C)(C)C)C(=O)NC(CC3CCC3)C(=O)C(=O)N)C; PubChem:10324367; ChEMBL ID: CHEMBL218394) is a 1:1 mixture of two diastereomers (SCH-534128 - active - and SCH-534129 - inactive). The inhibitor is clearly peptide like, containing three amino acid residues, mimicking the natural substrate of the protease. It has a molecular weight of 519.7 Da, contains 4 hydrogen bond donors, 5 hydrogen bond acceptors, and has an ALogP of 1.62.

Boceprevir is available as oral gelatin capsules of 200 mg. It has an apparent volume of distribution (Vd/F) of approximately 772 L, and, in patients who received a dose of 800 mg three times a day (the recommended daily dose is therefore a large 2.4 g (equivalent to 4,600 umol)), the exposure is characterised by an AUC of 5408, a Cmax of 1723 ng/mL and a Cmin of 88 ng/mL. Boceprevir should be administered with food, since food enhances its bioavailability by up to 65%. Human plasma protein binding (ppb) is approximately 75% following a single dose of boceprevir of 800 mg.

The primary metabolising route of boceprevir is through the aldo-ketoreductase (AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV (Pfam:PF00248). Boceprevir is eliminated with a mean plasma half-life (t1/2) of approximately 3.4 hours, and it has a mean total body clearance (CL/F) of approximately 161 L/hr.

Boceprevir is a strong inhibitor of CYP3A4, and therefore, other therapeutic agents primarily metabolised by these enzyme may prolong their therapeutic effect or adverse reactions, see prescribing information for the extensive list of drug-drug interactions, contraindications.

The license holder for Boceprevir is Merck & Co., and the full prescribing information can be found here. For more information, please visit the product website here.

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