Discovery of (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a Selective, Potent, Orally Bioavailable Hepatitis C Virus NS3 Protease Inhibitor:  A Potential Therapeutic Agent for the Treatment of Hepatitis C Infection

Venkatraman, Srikanth; Bogen, Stéphane; Arasappan, Ashok; Bennett, Frank; Chen, Kevin; Jao, Edwin; Liu, Yi‐Tsung; Lovey, Raymond G.; Hendrata, Siska; Huang, Yuhua; Pan, Weidong; Parekh, Tejal N.; Pinto, Patrick; Popov, Veljko; Pike, Russel; Ruan, Sumei; Santhanam, B.; Vibulbhan, Bancha; Wu, Wanli; Yang, Weiying; Kong, Jianshe; Liang, Xiang; Wong, Jesse K.; Liu, Rong; Butkiewicz, Nancy; Chase, Robert A.; Hart, Andrea; Agrawal, Sony; Ingravallo, Paul; Pichardo, John; Kong, Rong; Baroudy, Bahige M.; Malcolm, Bruce A.; Guo, Zhuyan; Prongay, Andrew; Madison, Vincent; Broske, Lisa; Cui, Xiaoming; Cheng, Kui; Hsieh, Yunsheng; Brisson, Jean-Marc; Prelusky, Danial; Korfmacher, Walter A.; White, Ronald E.; Bogdanowich-Knipp, Susan; Pavlovsky, Anastasia; Bradley, Prudence; Saksena, Anil K.; Ganguly, Ashit K.; Piwinski, John J.; Girijavallabhan, Viyyoor; Njoroge, F. George

doi:10.1021/jm060325b

Cited by 262 publications

(148 citation statements)

References 41 publications

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“…Under these conditions, ITMN-191, telaprevir, boceprevir, and ciluprevir displayed IC 50 s of 0.29 nM, 130 nM, 80 nM, and 0.73 nM, respectively, against a full-length genotype 1b NS3/4A reference protein (K2040) ( Table 1). The values determined here were similar to those previously described as K i values for these compounds against genotype 1 NS3/4A proteins (19,26,48). For inhibitors with slow/tight binding mechanisms, such as telapravir, boceprevir, and ITMN-191, the K i * is more relevant, as it takes into account the more stable and slowly dissociating complex.…”

Section: Resultssupporting

confidence: 82%

“…For inhibitors with slow/tight binding mechanisms, such as telapravir, boceprevir, and ITMN-191, the K i * is more relevant, as it takes into account the more stable and slowly dissociating complex. The K i * is 7 nM for telapravir (19,26,48), 14 nM for boceprevir (48), and 0.036 nM for . Full characterization of the inhibition kinetics of ITMN-191, including derivation of K i , K i *, and k off (compound dissociation rate) from microscopic rate constants, will be presented elsewhere (P. T. R. Rajagopalan, S. D. Seiwert, and K. Kossen, unpublished data).…”

Section: Resultsmentioning

confidence: 99%

“…The appreciable biochemical potency of ITMN-191 translates into significant antireplicon activity (Fig. 4), which is significantly greater than those of telaprevir (26) and boceprevir (48) and is 4-fold to 17-fold superior to TMC435350 (40). While the studies here suggest ITMN-191 and ciluprevir are equipotent against the replicon (19), other HCV genotype 1 replicon systems have indicated that ITMN-191 may be at least fivefold more potent than ciluprevir (12).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)

Seiwert¹,

Andrews

Jiang

et al. 2008

Antimicrob Agents Chemother

169

132

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)

Seiwert¹,

Andrews

Jiang

et al. 2008

Antimicrob Agents Chemother

169

132

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“…The synthesis of BI 201335 has been reported (20). Telaprevir and boceprevir were synthesized at Boehringer Ingelheim according to published procedures (37,41). Alpha interferon (IFN-␣) from human leukocytes and ribavirin were obtained from Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

Preclinical Characterization of BI 201335, a C-Terminal Carboxylic Acid Inhibitor of the Hepatitis C Virus NS3-NS4A Protease

White

Llinàs‐Brunet

Amad

et al. 2010

Antimicrob Agents Chemother

106

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BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K i values of 2.6 and 2.0 nM, respectively. K i values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC 50 s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection. Chronic hepatitis C virus (HCV) infection affects 130 to 170 million individuals worldwide (14). The etiologic agent is a small enveloped single-stranded RNA virus belonging to the Flaviviridae family, Hepacivirus genus (32). Although present in human populations for thousands of years, it was discovered only 20 years ago as the causative agent of non-A, non-B hepatitis (6). The HCV genome consists of approximately 9,600 bases, encoding a single polyprotein of approximately 3,000 amino acids, flanked by conserved 5Ј and 3Ј untranslated regions (UTRs). The viral polyprotein comprises four structural proteins followed by six nonstructural (NS) proteins that play essential roles in viral replication (25).One of the best-studied nonstructural proteins is NS3, a bifunctional protein that consists of an N-terminal protease domain and a C-terminal helicase domain (9). The protease domain has a trypsin-like fold with a flat and solvent-exposed substrate binding site (11,21). The central portion of the NS4A protein is integrated into the protein fold of the NS3 protease domain and is required for full activity (3). The NS3-NS4A (NS3 coexpressed with NS4A) protease plays a critical role in the maturation of the viral polyprotein precursor and was recognized early on as potential target for antiviral drugs (2). Indeed, the first direct acting antiviral agent to be studied in humans was the protease inhibitor BILN 2061, and two other protease inhibitors, telaprevir and boceprevir, are currently in phase III trials (10,1...

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“…The NS4A polypeptide acts as a cofactor of NS3 serine protease for efficient polyprotein processing (30). The HCV NS3-NS4A complex is a heterodimeric serine protease that has been considered a prime target for developing direct-acting antivirals (31,32), such as novel protease inhibitors of noncovalent macrocyclic simeprevir/TMC435 (33,34), covalent linear boceprevir (BOC) (35)(36)(37), and telaprevir analog (TVR) (38,39). From an immunologic point of view, the HCV NS2 to -4A proteins are major antigens in HCV vaccines, a few of which are currently in clinical trials for induction of a protective T-cell response against HCV infection (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus

Zhu

Liu

et al. 2016

J Virol

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A lack of immunocompetent-small-primate models has been an obstacle for developing hepatitis C virus (HCV) vaccines and affordable antiviral drugs. In this study, HCV/GB virus B (GBV-B) chimeric virus carrying the major nonstructural proteins NS2 to NS4A (HCV NS2 to -4A chimera) was produced and used to infect common marmosets, since HCV NS2 to NS4A proteins are critical proteases and major antigens. Seven marmosets were inoculated intrahepatically with HCV NS2 to -4A chimera RNA for primary infection or intravenously injected with chimera-containing serum for passage infection. Three animals used as controls were injected with phosphate-buffered saline (PBS) or GBV-B, respectively. Six of seven HCV NS2 to -4A chimera-infected marmosets exhibited consistent viremia and one showed transient viremia during the course of follow-up detection. All six infected animals with persistent circulating viremia presented characteristics typical of viral hepatitis, including viral RNA and proteins in hepatocytes and histopathological changes in liver tissue. Viremia was consistently detected for 5 to 54 weeks of follow-up. FK506 immunosuppression facilitated the establishment of persistent chimera infection in marmosets. An animal with chimera infection spontaneously cleared the virus in blood 7 weeks following the first inoculation, but viral-RNA persistence, low-level viral protein, and mild necroinflammation remained in liver tissue. The specific antibody and T-cell response to HCV NS3 in this viremia-resolved marmoset was boosted by rechallenging, but no viremia was detected during 57 weeks of follow-up. The chimera-infected marmosets described can be used as a suitable small-primate animal model for studying novel antiviral drugs and T-cell-based vaccines against HCV infection. H epatitis C virus (HCV) infection is a global health threat thatcauses chronic hepatitis and is associated with 78% of primary hepatocellular carcinoma (1). Currently, limitations of small-primate models hamper the development of HCV vaccines and affordable antiviral drugs. Chimpanzees have been used as a uniquely reliable animal for HCV infection in past decades (2), significantly contributing to defining the infection natural history, pathogenesis, immune response, and rechallenge of HCV (3-6). However, the utility of chimpanzees has been more and more restricted by ethical concerns, and though rare, the use of this primate model in medical studies is extremely costly (2). The nonprimate animal models simulating HCV infection might potentially be mimicked with rodent hepacivirus (RHV)-infected rats (7,8), canine hepacivirus (CHV)-infected dogs (9), and equine hepacivirus (EHCV) (nonprimate hepacivirus [NPHV])-infected horses (10). HCV infection in immunocompetent mice was reported in genetically humanized mouse CD81 and occludin (OCLN) (11,12). However, the differences in infection courses and immune responses fundamentally separate these mice from HCV-infected patients.Common marmosets (Callithrix jacchus), one of the New World small ...

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Cited by 262 publications

References 41 publications

Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)

Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)

Preclinical Characterization of BI 201335, a C-Terminal Carboxylic Acid Inhibitor of the Hepatitis C Virus NS3-NS4A Protease

Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus

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