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It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide (1,2). Clinical trials have demonstrated that, for the first time in human history, [...]

The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people (1). Current therapy relies upon a combination of pegylated interferon-a and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus (2,3). The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B (4). Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations ([EC.sub.50]) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 [log.sub.10] reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors., We designed a mechanistically unbiased approach based on chemical genetics to identify chemical starting points for interfering with HCV replication. Our differentiating strategy centred on the identification of compounds functionally [...]

The asymmetric synthesis of the core nucleus of the antitumor agent FR-900482 is presented. The scheme involves the cyclization of an aziridinyl radical into a functionalized indole nucleus. Two oxygen atoms were installed by selective Polonovski reaction and the Hootele-Dmitrienko rearrangement. The reaction conditions and mechanisms are presented.

Synthesis of azirino(2',3':3,4)pyrrolo(1, 2-a)indoles involves generation and cyclization of chiral carbon-centered aziridinyl radicals. A chiral aziridine carboxylic acid ester helps generate the carbon-centered aziridinyl radical. Bromo aziridines prepared from this radical undergo reductive cyclization in the presence of n-Bu3SnH, producing the indoles. Single-crystal X-ray studies indicate that these indoles have the same relative and absolute stereochemistry as the mitomycin C nucleus.

An efficient and practical synthetic protocol for the synthesis of 1,4-disubstituted pyrrolo[1,2- a ]pyrazine derivatives is described that originates from α-substituted pyrroloacetonitriles which, in turn, are readily available from aryl and alkyl aldehydes. The α-pyrroloacetonitriles were subjected to a Friedel–Crafts acylation with methyl chlorooxoacetate followed by reduction of the nitrile group under Pd-catalyzed hydrogenation conditions and finally aromatization with DDQ leading to the desired pyrrolo[1,2- a ]pyrazine derivatives. This method was generalized and successfully applied to various aryl, heteroaryl, and alkyl substrates. The developed protocol provides direct and convenient access to 1,4-disubstituted ring systems in moderate to good overall yields (51–68%) without the need for purification of the intermediates. Further functionalization via the stepwise halogenation (bromination, iodination) and nitration was also demonstrated. In addition, the potential of the ester functionality for elaboration was demonstrated by manipulating into heterocyclic ring systems, exemplified by conversion into benzoxazole derivatives. [ABSTRACT FROM AUTHOR]

A medicinal chemistry campaign thatwas conducted to address apotential genotoxic liability associated with an aniline-derived scaffoldin a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitoryactivity is described. Anilides 3band 3cwere used as vehicles to explore structural modifications that retainedantiviral potency while removing the potential for metabolism-basedunmasking of the embedded aniline. This effort resulted in the discoveryof a highly potent biarylimidazole chemotype that established a potencybenchmark in replicon assays, particularly toward HCV GT-1a, a strainwith significant clinical importance. Securing potent GT-1a activityin a chemotype class lacking overt structural liabilities was a criticalmilestone in the effort to realize the full clinical potential oftargeting the HCV NS5A protein. [ABSTRACT FROM AUTHOR]

The biphenyl derivatives 2and 3areprototypes of a novel class of NS5A replication complex inhibitorsthat demonstrate high inhibitory potency toward a panel of clinicallyrelevant HCV strains encompassing genotypes 1–6. However, thesecompounds exhibit poor systemic exposure in rat pharmacokinetic studiesafter oral dosing. The structure–activity relationship investigationsthat improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification ofthe highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was therealization that the arylglycine cap of 2could be replacedwith an alkylglycine derivative and still maintain the high inhibitorypotency of the series if accompanied with a stereoinversion, a findingthat enabled a rapid optimization of exposure properties. Compound 33had EC50values of 50 and 9 pM toward genotype-1aand -1b replicons, respectively, and oral bioavailabilities of 38–108%in preclinical species. Compound 33provided clinicalproof-of-concept for the NS5A replication complex inhibitor class,and regulatory approval to market it with the NS3/4A protease inhibitorasunaprevir for the treatment of HCV genotype-1b infection has recentlybeen sought in Japan. [ABSTRACT FROM AUTHOR]

Lead inhibitors that target the functionof the hepatitis C virus(HCV) nonstructural 5A (NS5A) protein have been identified by phenotypicscreening campaigns using HCV subgenomic replicons. The demonstrationof antiviral activity in HCV-infected subjects by the HCV NS5A replicationcomplex inhibitor (RCI) daclatasvir (1) spawned considerableinterest in this mechanistic approach. In this Perspective, we summarizethe medicinal chemistry studies that led to the discovery of 1and other chemotypes for which resistance maps to the NS5Aprotein and provide synopses of the profiles of many of the compoundscurrently in clinical trials. We also summarize what is currentlyknown about the NS5A protein and the studies using NS5A RCIs and labeledanalogues that are helping to illuminate aspects of both protein functionand inhibitor interaction. We conclude with a synopsis of the resultsof notable clinical trials with HCV NS5A RCIs. [ABSTRACT FROM AUTHOR]

The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log10 reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors. [ABSTRACT FROM AUTHOR]