P4 and P1′ optimization of bicycloproline P2 bearing tetrapeptidyl α-ketoamides as HCV protease inhibitors

Yip, Yvonne Y.; Victor, Frantz; Lamar, Jason; Johnson, Robert B.; Wang, Q. May; Glass, John I.; Yumibe, Nathan; Wakulchik, Mark; Munroe, John E.; Chen, Shuhui

doi:10.1016/j.bmcl.2004.07.007

Cited by 45 publications

(24 citation statements)

References 19 publications

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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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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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“…VX-950 was prepared at Vertex Pharmaceuticals, Incorporated using a method described previously (46). BILN 2061 was discovered at Boehringer Ingelheim, and its synthesis has been described (7).…”

Section: Methodsmentioning

confidence: 99%

VX-950, a Novel Hepatitis C Virus (HCV) NS3-4A Protease Inhibitor, Exhibits Potent Antiviral Activities in HCV Replicon Cells

Lin

Perni

Kwong

et al. 2006

Antimicrob Agents Chemother

187

134

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The NS3-4A serine protease of hepatitis C virus (HCV) is essential for viral replication and therefore has been one of the most attractive targets for developing specific antiviral agents against HCV. VX-950, a highly selective, reversible, and potent peptidomimetic inhibitor of the HCV NS3-4A protease, is currently in clinical development for the treatment of hepatitis C. In this report, we describe the in vitro characterization of anti-HCV activities of VX-950 in subgenomic HCV replicon cells. Incubation with VX-950 resulted in a timeand dose-dependent reduction of HCV RNA and proteins in replicon cells. Moreover, following a 2-week incubation with VX-950, a reduction in HCV RNA levels of 4.7 log 10 was observed, and this reduction resulted in elimination of HCV RNA from replicon cells, since there was no rebound in replicon RNA after withdrawal of the inhibitor. The combination of VX-950 and alpha interferon was additive to moderately synergistic in reducing HCV RNA in replicon cells with no significant increase in cytotoxicity. The benefit of the combination was sustained over time: a 4-log 10 reduction in HCV RNA level was achieved following a 9-day incubation with VX-950 and alpha interferon at lower concentrations than when either VX-950 or alpha interferon was used alone. The combination of VX-950 and alpha interferon also suppressed the emergence of in vitro resistance mutations against VX-950 in replicon cells.

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“…discovered another promising HCV protease inhibitor 4B endowed with superior antiviral activity relative to all previously reported inhibitors I [9], II [10], and III [11] as shown in (Fig. 1).…”

Section: Discussionmentioning

confidence: 91%

“…In the same vein, chemists from Eli Lilly focused their efforts on the design and systematic optimizations (P2 through P4) of a novel class of bicycloproline P2 bearing α-ketoamides as HCV protease inhibitors [8]. Towards this end, a number of recent papers from this institution detailed the discovery of various P2 bicycloproline incorporated α-ketoamide based NS3-4A inhibitors such as I [9], II [10], and III [11]. To our satisfaction, many members of such tetrapeptidyl α-ketoamide based inhibitors (e.g., I and II as shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl α-Ketoamide Based HCV Protease Inhibitors

Chen¹,

Lamar²,

Yip³

et al. 2005

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We describe herein tetrapeptidyl α-ketoamide 4A based systematic P1 modifications alone or/and in combination with further P1' variations. These SAR efforts led to the discovery of a number of potent and selective HCV NS3 protease inhibitors such as 4B, 9, and 12 endowed with impressive cellular activity as measured in the replicon assay and very good therapeutic indexes. On the basis of its overall profile, compound 4B (VX-950) has been selected for human clinical trials.

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P4 and P1′ optimization of bicycloproline P2 bearing tetrapeptidyl α-ketoamides as HCV protease inhibitors

Cited by 45 publications

References 19 publications

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

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

VX-950, a Novel Hepatitis C Virus (HCV) NS3-4A Protease Inhibitor, Exhibits Potent Antiviral Activities in HCV Replicon Cells

P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl α-Ketoamide Based HCV Protease Inhibitors

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P4 and P1′ optimization of bicycloproline P2 bearing tetrapeptidyl α-ketoamides as HCV protease inhibitors

Cited by 45 publications

References 19 publications

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

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

VX-950, a Novel Hepatitis C Virus (HCV) NS3-4A Protease Inhibitor, Exhibits Potent Antiviral Activities in HCV Replicon Cells

P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl &#945;-Ketoamide Based HCV Protease Inhibitors

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P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl α-Ketoamide Based HCV Protease Inhibitors