[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Egypt has the highest prevalence of hepatitis C infection in the world, with 90% due to HCV genotype-4 (gt-4). Increasing HCV-related morbidity in Egypt presents an urgent need for highly curative, safe and affordable therapies. We report results from a Phase 3 registrational trial in Egyptian HCV gt-4 patients, assessing the combination of ravidasvir (RDV), a pan-genotypic HCV NS5A inhibitor, and sofosbuvir (SOF), a nucleotide HCV NS5B polymerase inhibitor, with or without ribavirin (RBV). METHODS: Key inclusion criteria were age 18-65 yr, HCV gt-4 infection, serum HCV RNA >4 log10 IU/mL, and absence of decompensated cirrhosis or other causes of liver disease. Patients were enrolled into 3 groups: treatment-naïve non-cirrhotic and cirrhotic, by Fibroscan & FIB-4 score (Group 1); interferon (IFN)-experienced non-cirrhotic (Group 2); and IFN-experienced cirrhotic (Group 3). Groups 1 and 2 were treated with RDV 200 mg QD + SOF 400 mg QD for 12 wk, randomized 1:1 to additional RBV (weight-based) or no RBV. Group 3 patients all received RDV+SOF+RBV and were randomized 1:1 to 12 wk vs. 16 wk of treatment. The primary endpoint is sustained virologic response (SVR), defined as serum HCV RNA below the lower limit of detection (LLD <12 IU/mL by the Abbott Real-Time™ PCR assay) at 12 wk post-treatment (SVR12). RESULTS: This study is fully enrolled with 300 patients (150 in Group 1, 80 in Group 2, and 70 in Group 3); 283 patients had completed treatment at the time of this abstract. Study treatment has been generally well tolerated, with one serious adverse event possibly attributed to study drug (transient episode of symptomatic bradycardia). The most common adverse events are headache and fatigue. HCV RNA decreased by ~6 logs in all groups by Wk 1, with 94% of patients HCV RNA undetectable by Wk 4. Of the 263 patients who have reached 4 wk post-treatment, 260 (99%) had RNA <LLD (SVR4); also, 231 of 235 (98%) have achieved SVR8 and 153 of 159 (96%) have achieved SVR12 to date. The addition of RBV did not improve response. The 6 treatment failures are all cirrhotic patients, one patient had only 8 weeks of treatment due to the bradycardia episode, and 5 patients relapsed after completing treatment. None of the non-cirrhotic patients have experienced a relapse. Near-final SVR4, SVR8, and SVR12 data will be presented during the meeting. Conclusions: To our knowledge, this is the largest IFN free clinical trial in HCV gt-4 patients. Treatment with RDV+SOF±RBV has been well-tolerated and shows high sustained response rates in a large population of Egyptian patients, regardless of previous treatment status or underlying cirrhosis.
[Show abstract][Hide abstract] ABSTRACT: Graphical abstract
This letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have shown low single-digit nM potency in gt-1a replicon and double-digital pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration.
No preview · Article · Dec 2014 · Bioorganic & Medicinal Chemistry Letters
[Show abstract][Hide abstract] ABSTRACT: This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.
No preview · Article · Oct 2014 · Bioorganic & Medicinal Chemistry Letters
[Show abstract][Hide abstract] ABSTRACT: BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase.
BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and
1b at 50% effective concentrations (EC50s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a. Potency against genotype
6a showed more variability (9 to 125 nM), and activity was weaker against genotype 2 (EC50, 87 to 925 nM). Specificity was demonstrated by the absence of activity (EC50s of >4 μM) against a panel of mammalian viruses, and cytotoxic concentrations (50%) were >3,000-fold above the HCV EC50. Resistance substitutions selected by BMS-791325 in genotype 1 replicons mostly mapped to a single site, NS5B amino acid
495 (P495A/S/L/T). Additive or synergistic activity was observed in combination studies using BMS-791325 with alfa interferon
plus ribavirin, inhibitors of NS3 protease or NS5A, and other classes of NS5B inhibitor (palm site 2-binding or nucleoside
analogs). Plasma and liver exposures in vivo in several animal species indicated that BMS-791325 has a hepatotropic disposition (liver-to-plasma ratios ranging from 1.6-
to 60-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥10-fold above the
inhibitor EC50s observed with HCV genotype 1 replicons. These findings support the evaluation of BMS-791325 in combination regimens for
the treatment of HCV. Phase 3 studies are ongoing.
[Show abstract][Hide abstract] ABSTRACT: The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
Full-text · Article · Feb 2014 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
Full-text · Article · Feb 2014 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
No preview · Article · Feb 2014 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: A series of highly potent HIV-1 attachment inhibitors with a 4-fluoro-6-azaindole core heterocycle that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (12a,b), C-linked heterocycles (12c-l) and N-linked heterocycles (12m-u) provided compounds with sub-nanomolar potency in a pseudotype infectivity assay and good pharmacokinetic profiles in vivo. A predictive model was developed from the initial SAR in which the potency of the analogs correlated with the ability of the substituent in the 7-position of the azaindole to adopt a coplanar conformation by either forming internal hydrogen bonds or avoiding repulsive substitution patterns. 1-(4-Benzoyl-piperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-ethane-1,2-dione (BMS-585248, 12m) exhibited much improved in vitro potency and pharmacokinetic properties than the previous clinical candidate BMS-488043 (1). The predicted low clearance in humans, modest protein binding and good potency in the presence of 40% human serum for 12m led to its selection for human clinical studies.
No preview · Article · Jan 2013 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Asunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients
chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor
daclatasvir. ASV competitively binds to the NS3/4A protease complex, with Ki values of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity
was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel
of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes
1 and 4, with 50% effective concentrations (EC50s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC50, 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC50, >12 μM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with
alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposures in vivo in several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40-
to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the
inhibitor EC50s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility
in a combination with other anti-HCV agents in the treatment of HCV-infected patients.
Full-text · Article · Aug 2012 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.
No preview · Article · Mar 2012 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Attachment inhibitors (AI) are a novel class of HIV-1 antivirals, with little information available on clinical resistance. BMS-488043 is an orally bioavailable AI that binds to gp120 of HIV-1 and abrogates its binding to CD4(+) lymphocytes. A clinical proof-of-concept study of the AI BMS-488043, administered as monotherapy for 8 days, demonstrated significant viral load reductions. In order to examine the effects of AI monotherapy on HIV-1 sensitivity, phenotypic sensitivity assessment of baseline and postdosing (day 8) samples was performed. These analyses revealed that four subjects had emergent phenotypic resistance (a 50% effective concentration [EC(50)] >10-fold greater than the baseline value) and four had high baseline EC(50)s (>200 nM). Population sequencing and sequence determination of cloned envelope genes uncovered five gp120 mutations at four loci (V68A, L116I, S375I/N, and M426L) associated with BMS-488043 resistance. Substitution at the 375 locus, located near the CD4 binding pocket, was the most common (maintained in 5/8 subjects at day 8). The five substitutions were evaluated for their effects on AI sensitivity through reverse genetics in functional envelopes, confirming their role in decreasing sensitivity to the drug. Additional analyses revealed that these substitutions did not alter sensitivity to other HIV-1 entry inhibitors. Thus, our studies demonstrate that although the majority of the subjects' viruses maintained sensitivity to BMS-488043, substitutions can be selected that decrease HIV-1 susceptibility to the AI. Most importantly, the substitutions described here are not associated with resistance to other approved antiretrovirals, and therefore, attachment inhibitors could complement the current arsenal of anti-HIV agents.
Full-text · Article · Nov 2010 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: BMS-488043 is a novel and unique oral small-molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1)
to CD4+ lymphocytes. The antiviral activity, pharmacokinetics, viral susceptibility, and safety of BMS-488043 were evaluated in an
8-day monotherapy trial. Thirty HIV-1-infected study subjects were randomly assigned to sequential, safety-guided dose panels
of 800 and 1,800 mg BMS-488043 or a matched placebo in a 4:1 ratio, and the drug was administered every 12 h with a high-fat
meal for 7 days and on the morning of day 8. Dose-related, albeit less-than-dose-proportional, increases in plasma BMS-488043
concentrations were observed. Mean plasma HIV-1 RNA decreases from the baseline for the BMS-488043 800- and 1,800-mg dose
groups on day 8 were 0.72 and 0.96 log10 copies/ml, respectively, compared with 0.02 log10 copies/ml for the placebo group. A lower baseline BMS-488043 50% effective concentration (EC50) in the active-treatment groups was predictive of a greater antiviral response. Although absolute drug exposure was not associated
with an antiviral response, the trough concentration (Ctrough), adjusted by the baseline EC50 (Ctrough/EC50), was associated with antiviral activity. During dosing, four subjects experienced >10-fold reductions in viral susceptibility
to BMS-488043, providing further support of the direct antiviral mechanism of BMS-488043. BMS-488043 was generally safe and
well tolerated. These results suggest that further development of this novel class of oral HIV-1 attachment inhibitors is
Full-text · Article · Nov 2010 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Treatment with HIV attachment inhibitors (AIs) can select for escape mutants throughout the viral envelope. We report on three such mutations: F423Y (gp120 CD4 binding pocket) and I595F and K655E (gp41 ectodomain). Each displayed decreased sensitivity to the AI BMS-488043 and earlier generation AIs, along with increased sensitivity to the broadly neutralizing antibodies 2F5 and 4E10, without affecting the rate of viral entry or sensitivity to the entry inhibitors AMD-3100 and Enfuvirtide. We also observed that I595F did not substantially increase envelope sensitivity to HIV-infected patient sera. Based on these observations, we propose that although F423Y, I595F and K655E may all affect the presentation of the 2F5 and 4E10 epitopes, natural immune mimicry is rare only for the I595F effect. Thus, it seems that in addition to restricting AI resistance development, incorporation of I595F into an appropriate vehicle could elicit a novel antiviral response to improve vaccine efficacy.
[Show abstract][Hide abstract] ABSTRACT: 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-alpha 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 (EC(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(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.