Boceprevir

Absorption

Boceprevir reaches peak plasma concentration 2 hours after administration . Absolute bioavailability has not been determined. When taken with food exposure increases up to 65%. In capsule, Boceprevir consists of two diaseromers in a 1:1 ratio. In plasma this ratio changes to 2:1 favoring the active diastereomer.

Toxicity

The most commonly reported adverse reactions in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when Boceprevir was used in combination with Ribavirin and Peginterferon alfa-2a/Peginterferon alfa-2b .

Description

In May 2011, the U.S. FDA approved boceprevir (SCH-503034), to be given in combination with peginterferon alfa plus ribavirin, for the treatment of patients with chronic hepatitis C genotype 1 viral infection. Boceprevir and telaprevir are the first hepatitis C virus (HCV) protease inhibitors to be approved for the treatment of HCV infection. Boceprevir is an inhibitor of HCV NS3-4A protease, an essential enzyme required by HCV for posttranslational processing of viral proteins into their mature forms. Boceprevir binds covalently, but reversibly, to the active site serine by addition of the hydroxyl group to the keto-amide functionality. Boceprevir inhibits HCV NS3-4A protease with a Ki of 14 nM. In cell culture, the EC₅₀ of boceprevir was 200 nM for an HCV replicon constructed from genotype 1b. Boceprevir was two-to threefold less potent against HCV replicon from genotypes 1a, 2, and 3. The potency of boceprevir decreased threefold in the presence of human serum. Boceprevir was discovered through a series of systematic truncations and modifications of a keto-amide undecapeptide lead molecule.
Boceprevir is synthesized by coupling of 3-amino-4- cyclobutyl-2-hydroxybutyramide or the related oxobutyramide with a cyclopropyl-pyrrolidine carboxylic acid intermediate. The pyrrolidine derivative can be prepared via cyclopropanation of a bicyclic lactam derivative or by conversion of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid to the pyrrolidine in a multistep route. Boceprevir is a 1:1 mixture of diastereomers at the readily epimerizable position a to the keto group.

Description

Boceprevir is an inhibitor of hepatitis C virus (HCV) non-structural protease 3/4A (NS3/4A; K_i = 14 nM for the HCV genotype 1b enzyme). Boceprevir inhibits HCV replication in Huh7 cells (EC₅₀ = 200 nM). It also inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^pro; K_i = 1.8 μM) and reduces cytopathic effects of SARS-CoV-2 in Vero cells (EC₅₀ = 1.31 μM). Formulations containing boceprevir have been used in the treatment of HCV.

Chemical properties

Off-White to Pale Yellow Solid

Originator

Merck/Schering (United States)

The Uses of Boceprevir

An NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection. It is a COVID19-related research product.

Background

Boceprevir is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients . Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as Boceprevir. Boceprevir is an inhibitor of NS3/4A, a serine protease enzyme, encoded by HCV genotypes 1 and 4 . These enzymes are essential for viral replication and serve to cleave the virally encoded polyprotein into mature proteins like NS4A, NS4B, NS5A and NS5B . The barrier for develoment of resistance to NS3/4A inhibitors is lower than that of NS5B inhibitors, another class of DAAs . Subtitutions at amino acid positions 155, 156, or 168 are known to confer resistance. The substitutions of the enzyme's catalytic triad consisting of H58, D82, and S139 are also likely to alter the affinity of the drug for NS3/4A or the activity of the enzyme itself. Despite this disadvantage Boceprevir is still effective against HCV when paired with Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b.
In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) do not reccomend Boceprevir in combination with Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b as first line therapy for Hepatitis C . Boceprevir, Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b are used with the intent to cure, or achieve a sustained virologic response (SVR), after 48 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality .
Boceprevir is available as a fixed dose product (tradename Victrelis) used for the treatment of chronic Hepatitis C. Approved in May 2011 by the FDA, Victrelis is indicated for the treatment of HCV genotype 1 in combination with Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b . Victrelis is no longer widely used as interferon-free therapies have been developed.

Indications

Boceprevir, when used in combination with Ribavirin, Peginterferon alfa-2a, and Peginterferon alfa-2b is indicated for use in the treatment of chronic HCV genotype 1 infection in adults .

Definition

ChEBI: A synthetic tripeptide consisting of N-(tert-butylcarbamoyl)-3-methyl-L-valyl, a cyclopropyl-fused prolyl and 3-amino-4-cyclobutyl-2-oxobutanamide residues joined in sequence. Used for treatment of chronic h patitis C virus genotype 1 infection.

brand name

Victrelis

Pharmacokinetics

Boceprevir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotype 1 .

Clinical Use

Boceprevir is an oral inhibitor of HCV NS3/4A protease for the treatment of the chronic hepatitis C genotype infection. It is approved as combination therapy with Peg-IFN-alpha and ribavarin to treat adult patients with compensated liver diseasewhoare either treatment naive or who have experienced prior failed therapy with interferon and ribavarin. Boceprevir was initially discovered by Schering-Plough and developed and marketed by Merck & Co. since its acquisition of Schering-Plough in 2009. Several publications have highlighted the discovery of this drug, which evolved from a potent initial undecapeptide lead structure to boceprevir (VII) as a drug candidate with potent activity and desirable PK properties.

Synthesis

Several publications and patents including process patents describing the preparation of key fragments and a full synthesis of boceprevir, have been published. Retrosynthetically, the drug can be broken down into 3 or 4 key fragments and assembled in a convergent synthesis as depicted in the scheme.


Synthesis of t-butyl urea fragment 55 began with esterification of t-butyl amino acid 58 with TMSCl and triethylamine to give silyl ester 59. Silyl ester 59 was then reacted with t-butyl isocyanate 60 to provide urea 55 in 74¨C89% (2-steps).

Although several routes for the preparation of the azbicyclo[ 3.1.0]hexane ester 56 have been disclosed, the most recent process-scale synthesis of this heterocyclic core was accomplished using enzymatic desymmetrization of readily available azabicyclo[ 3.1.0]hexane 61(the scheme). This was accomplished through the enzymatic oxidation of 61 followed by trapping of the resulting imine 62 with bisulfate to give the corresponding sulfonate 63. Sulfonate 63 was attained under manufacturing conditions in 95% and 99% ee. Without isolation, the sulfonate salt was reacted with sodium cyanide in cyclopentyl methyl ether providing trans nitrile 64 in 90% yield from 61, presumably through an elimination of the sulfonate to regenerate imine 62, followed by addition of the nitrile group from the opposite face of the dimethylcyclopropyl group. Nitrile 64 was reacted under Pinner conditions (HCl, MeOH) to give ester salt 56 in 56% overall yield with greater than 99% ee after recrystallization from MTBE.
Although several preparations of cyclobutyl amides 57 have been disclosed, the process scale preparation is described in the scheme. Benzophenone-derived imine 65 was alkylated with bromomethylcyclobutane in the presence of base to give the alkylated intermediate, which was immediately treated in situ with HCl to furnish aminoester 66. This aminoester was then protected as the Boc-carbamate 67 prior to reduction of the ester to provide the corresponding alcohol 68 after crystallization from heptane in 43% overall yield. This alcohol was then oxidized with TEMPO, sodium bromide and sodium hypochlorite in DCM at 5 to 0??C to give aldehyde 69 in 91% yield. After exchanging solvents, aldehyde 69 was treated with acetone cyanohydrin at room temperature to provide intermediate 70 which, after treatment with potassium carbonate to wash off excess cyanohydrin, was hydrolyzed with hydrogen peroxide at 40??C to give 90% of amide 71. Hydroxyl amide 71 was deprotected under acidic conditions to give the hydrochloride salt 73. Alcohol 71 was also oxidized using EDCI, DMSO and dichloroacetic acid in ethyl acetate to afford the keto amide 72 in 70% yield. Subsequent treatment with HCl in isopropyl alcohol provided salt 57 in 91% yield.

With all four key fragments in hand, the final target was rapidly assembled in a convergent manner as described in the scheme. Carboxylic acid fragment 55 was first coupled to azbicyclo[ 3.2.1]cyclohexane amine ester salt 56 using EDCI as the coupling reagent under basic conditions to give amide 74. Hydrolysis of the methyl ester with lithium hydroxide followed by salt formation gave rise to carboxylate salt 75 in 90% overall yield. Under acidic conditions, salt 75 was coupled directly with cyclobutyl keto amide salt 57 in the presence of EDCI, HOBt and N-methylmorpholine in acetonitrile to give, after acidic and basic work-ups, boceprevir (VII) in 85¨C90% yield. Alternatively, salt 75 could be coupled with the cyclobutyl alcohol amide salt 73 using EDCI, HOBt and diisopropylethyamine (DIPEA) to give alcohol 76 in 90% yield after acid and base work-ups and crystallization. Oxidation of alcohol intermediate 76 with TEMPO and NaOCl in the presence of KBr also furnished boceprevir (VII) in 93% yield.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration possibly reduced by rifampicin - avoid. Anticoagulants: avoid with apixaban. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone - avoid. Antifungals: concentration increased by ketoconazole. Antimalarials: avoid with artemether and lumefantrine.
Antipsychotics: avoid pimozide; possibly increases lurasidone and quetiapine concentration - avoid.
Antivirals: reduces concentration of atazanavir; avoid with daclatasvir, darunavir, fosamprenavir and lopinavir; concentration of both drugs reduced with ritonavir.
Anxiolytics and hypnotics: increased oral midazolam concentration - avoid.
Ciclosporin: concentration of ciclosporin increased.
Cilostazol: possibly increases cilostazol concentration.
Cytotoxics: possibly increases bosutinib concentration - avoid or reduce bosutinib dose; avoid with dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, olaparib, pazopanib, sorafenib and sunitinib; reduce dose of ruxolitinib.
Domperidone: possible increased risk of ventricular arrhythmias - avoid.
Ergot alkaloids: avoid concomitant use.
Guanfacine: concentration possibly increased, halve guanfacine dose.
Lipid-regulating drugs: enhances effects and toxicity of atorvastatin, reduce atorvastatin dose; increases pravastatin concentration; avoid with simvastatin.
Oestrogens: possibly causes contraception failure.
Sirolimus: possibly increases sirolimus concentration.
Tacrolimus: concentration of tacrolimus increased, reduce tacrolimus dose.

Metabolism

Bocepravir is primarily metabolized via the aldo-ketoreductase-mediated pathway producing a diastereomeric mix of metabolites at a 4 fold greater exposure than the parent compound . Boceprevir also undergoes oxidative metabolism via CYP3A4/5, although to a lesser extent.

Metabolism

Boceprevir mainly undergoes metabolism through the aldo-ketoreductase mediated pathway to ketone-reduced metabolites that are inactive against HCV. After a single 800 mg oral dose of 14C-boceprevir, the most abundant circulating metabolites were a diasteriomeric mixture of ketone-reduced metabolites with a mean exposure approximately 4-fold greater than that of boceprevir. Boceprevir also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5. Mainly excreted by the liver - approximately 79% and 9% of the dose was excreted in faeces and urine, respectively, with approximately 8% and 3% eliminated as boceprevir in faeces and urine.

References

1) Malcom et al. (2006), SCH 503034, a Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease, Suppresses Polyprotein Maturation and Enhances the Antiviral Activity of Alpha Interferon in Replicon Cells; Antimicrob. Agents Chemother., 50 1013 2) Ma et al. (2020), Boceprevir, GC-376, and Calpain Inhibitors II, XII Inhibit SARS-CoV-2 Viral Replication by Targeting the Viral Main Protease; Cell Res.?30?678