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Synthetic Challenges in the Assembly of Macrocyclic HCV NS3/NS4A Protease Inhibitors: The Case of BILN 2061 and Its Analogs

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Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 44)

Abstract

The virally encoded serine protease NS3/NS4A is essential for the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The quest for the discovery of antiviral agents targeting the NS3/NS4A was initiated with a substrate-based hexapeptide as the lead structure. Evaluation of the conformational pre-organization of this ligand to the bioactive conformation led to the design of macrocyclic peptides, typified by the antiviral agents BILN 2061. Today, closely related analogs of BILN 2061 represent an important class of human therapeutics for the treatment of HCV infection. The critical steps in the synthesis of these compounds involves the cyclization of a tripeptide diene, containing a (1R,2S)-vinyl aminocyclopropylcarboxylate residue, via ring-closing metathesis (RCM). Conformational factors, ligand effects, and reaction conditions were evaluated, and a protocol was developed for the efficient production of these peptidomimetics in high yield and diastereomeric purity. The assembly of these challenging molecules and the key optimization studies are described.

Keywords

Hepatitis C virus Macrocyclic peptides NS3/NS4A protease inhibitors 

Abbreviations

Ac

Acetyl

ACCA

1-Aminocyclopropanecarboxylic acid

API

Active pharmaceutical ingredient

aq

Aqueous

BI

Boehringer Ingelheim

Bn

Benzyl

Boc

tert-Butoxycarbonyl

cod

Cyclooctadiene

Cy

Cyclohexyl

DEAD

Diethyl azodicarboxylate

DIAD

Diisopropyl azodicarboxylate

DIPEA

N,N-Diisopropylethylamine

DMF

Dimethylformamide

(S,S)-Et-DUPHOS

1,2-Bis[(2S,5S)-2,5-diethylphospholano]benzene

EC50

Half maximal effective concentration

equiv

Equivalent(s)

Et

Ethyl

FDA

Food and Drug Administration

h

Hour(s)

HCV

Hepatitis C virus

HPLC

High-performance liquid chromatography

HTS

High-throughput screening

i-Bu

Isobutyl

IC50

Half maximal inhibitory concentration

IFN-α

Pegylated interferon alpha

KHMDS

Potassium hexamethyldisilazide, potassium bis(trimethylsilyl)amide

LC–MS

Liquid chromatography–mass spectrometry

LiHMDS

Lithium hexamethyldisilazide, lithium bis(trimethylsilyl)amide

Me

Methyl

mol

Mole(s)

MTBE

Methyl tert-butyl ether

n-Bu

Butyl

NMR

Nuclear magnetic resonance

NS3

Nonstructural protein 3

Ph

Phenyl

PNBA

p-Nitrobenzoic

ppm

Parts per million

RCM

Ring-closing metathesis

RNA

Ribonucleic acid

ROESY

Rotating-frame Overhauser effect spectroscopy

rt

Room temperature

SAR

Structure–activity relationships

SN2

Substitution nucleophilic (bimolecular)

TBTU

N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate

t-Bu

tert-Butyl

Tf

Trifluoromethanesulfonyl (triflyl)

THF

Tetrahydrofuran

TON

Turnover number

Vinyl ACCA

1-Amino-2-vinylcyclopropanecarboxylic acid

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of ChemistryMcGill UniversityMontrealCanada

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