RESUMEN
Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/química , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Dominios Proteicos/efectos de los fármacos , Piridinas/farmacología , Pirroles/farmacología , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/química , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Elementos de Facilitación Genéticos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Piridinas/efectos adversos , Piridinas/toxicidad , Pirroles/efectos adversos , Pirroles/toxicidad , Ratas , Receptores Androgénicos/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.
Asunto(s)
Proteínas Nucleares/antagonistas & inhibidores , Piridonas/química , Factores de Transcripción/antagonistas & inhibidores , Animales , Sitios de Unión , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Ratones , Microsomas/metabolismo , Simulación de Dinámica Molecular , Mieloma Múltiple/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Estructura Terciaria de Proteína , Piridonas/farmacocinética , Piridonas/farmacología , Piridonas/uso terapéutico , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Trasplante HeterólogoRESUMEN
An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.
Asunto(s)
Antineoplásicos/química , Proteínas Nucleares/antagonistas & inhibidores , Pirroles/química , Factores de Transcripción/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Semivida , Humanos , Ratones , Simulación de Dinámica Molecular , Mieloma Múltiple/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Pirroles/síntesis química , Pirroles/farmacocinética , Pirroles/uso terapéutico , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Trasplante HeterólogoRESUMEN
Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Hepacivirus/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Bencimidazoles/farmacocinética , Perros , Genotipo , Halogenación , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatitis C/tratamiento farmacológico , Humanos , Ratones , Ratas , Replicón/efectos de los fármacos , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
The synthesis and structure-activity relationships of a novel aryl uracil series which contains a fused 5,6-bicyclic ring unit for HCV NS5B inhibition is described. Several analogs display replicon cell culture potencies in the low nanomolar range along with excellent rat pharmacokinetic values.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Uracilo/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Hepacivirus/enzimología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Ratas , Relación Estructura-Actividad , Uracilo/farmacología , Proteínas no Estructurales Virales/metabolismoRESUMEN
Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified 24, a structural analog of the potent GPX4 inhibitor RSL3, that has much better plasma stability (t1/2 > 5 h in mouse plasma). The bioavailability of 24 provided efficacious plasma drug concentrations with IP dosing, thus enabling in vivo studies to assess tolerability and efficacy. An efficacy study in mouse using a GPX4-sensitive tumor model found that doses of 24 up to 50 mg/kg were tolerated for 20 days but had no effect on tumor growth, although partial target engagement was observed in tumor homogenate.
Asunto(s)
Ferroptosis , Neoplasias , Ratones , Animales , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Disponibilidad BiológicaRESUMEN
Aryl dihydrouracil derivatives were identified from high throughput screening as potent inhibitors of HCV NS5B polymerase. The aryl dihydrouracil derivatives were shown to be non-competitive with respect to template RNA and elongation nucleotide substrates. They demonstrated genotype 1 specific activity towards HCV NS5B polymerases. Structure activity relationships and genotype specific activities of aryl dihydrouracil derivatives suggested that they bind to the palm initiation nucleotide pocket, a hypothesis which was confirmed by studies with polymerases containing mutations in various inhibitor binding sites. Therefore, aryl dihydrouracil derivatives represent a novel class of palm initiation site inhibitors of HCV NS5B polymerase.
Asunto(s)
Inhibidores de Proteasas/química , Uracilo/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sustitución de Aminoácidos , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Cinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Sitio de Iniciación de la Transcripción , Uracilo/síntesis química , Uracilo/química , Uracilo/farmacología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex.
Asunto(s)
Antivirales , Tratamiento Farmacológico de COVID-19 , Descubrimiento de Drogas , Antivirales/farmacología , Vacunas contra la COVID-19 , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Humanos , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Proteínas Virales/metabolismoRESUMEN
BACKGROUND/AIM: The therapeutic potential of bromodomain and extra-terminal motif (BET) inhibitors in hematological cancers has been well established in preclinical and early-stage clinical trials, although as of yet, no BETtargeting agent has achieved approval. To add insight into potential response to mivebresib (ABBV-075), a broadspectrum BET inhibitor, co-clinical modeling of individual patient biopsies was conducted in the context of a Phase I trial in acute myeloid leukemia (AML). MATERIALS AND METHODS: Co-clinical modeling involves taking the patient's biopsy and implanting it in mice with limited passage so that it closely retains the original characteristics of the malignancy and allows comparisons of response between animal model and clinical data. Procedures were developed, initially with neonate NOD/Shi-scid-IL2rγnull (NOG) mice and then optimized with juvenile NOG-EXL as host mice, eventually resulting in a robust rate of engraftment (16 out of 26, 62%). RESULTS: Results from the co-clinical AML patient-derived xenograft (PDX) modeling (6 with >60% inhibition of bone marrow blasts) were consistent with the equivalent clinical data from patients receiving mivebresib in monotherapy, and in combination with venetoclax. The modeling system also demonstrated the activity of a novel BD2-selective BET inhibitor (ABBV-744) in the preclinical AML setting. Both agents were also highly effective in inhibiting blast counts in the spleen (10/10 and 5/6 models, respectively). CONCLUSION: These findings confirm the validity of the model system in the co-clinical setting, establish highly relevant in vivo models for the discovery of cancer therapy, and indicate the therapeutic value of BET inhibitors for AML and, potentially, myelofibrosis treatment.
Asunto(s)
Leucemia Mieloide Aguda , Piridonas , Animales , Línea Celular Tumoral , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Piridonas/farmacología , Piridonas/uso terapéutico , SulfonamidasRESUMEN
A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays.
Asunto(s)
Benzotiadiazinas/farmacología , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Benzotiadiazinas/química , Hepacivirus/enzimología , Hepacivirus/fisiología , Inhibidores de Proteasas/química , Replicación ViralRESUMEN
With the morbidity and mortality associated with the COVID-19 pandemic that we are witnessing this year, the risks posed by emerging viral diseases to global health are all too obvious. This pandemic highlights the importance of antiviral drug discovery, which targets emerging viral pathogens, as well as existing pathogenic viruses that undergo continuous evolution. Drug discovery and development is a long and resource intensive process; however, the use of biomarkers can accelerate clinical development of antivirals by providing information regarding diagnosis of specific viral infections, status of infection, potential safety parameters, and antiviral responses. In clinical practice, many of the biomarkers initially utilized to support clinical development are also used for patient care. While viral load is a standard and essential biomarker used to detect the desired viral suppression induced by an antiviral agent, it has become apparent that additional biomarkers, whether related to the virus, the host or as a consequence of the drug's mechanistic effects, are also important for monitoring clinical outcomes associated with an antiviral therapy. This review summarizes the biomarkers used in the clinical development (as well as in clinical practice, where appropriate) of antiviral therapies for hepatitis C virus, hepatitis B virus, human immunodeficiency virus, and severe acute respiratory syndrome coronavirus 2.
Asunto(s)
Antivirales/uso terapéutico , Biomarcadores/análisis , Virosis/tratamiento farmacológico , Animales , Antivirales/farmacología , COVID-19/virología , Ensayos Clínicos como Asunto , Humanos , SARS-CoV-2/fisiología , Tratamiento Farmacológico de COVID-19RESUMEN
Dual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain of the four BET family proteins. In contrast to the broad antiproliferative activities observed with dual bromodomain BET inhibitors, ABBV-744 displayed significant antiproliferative activities largely although not exclusively in cancer cell lines derived from acute myeloid leukemia and androgen receptor positive prostate cancer. Studies in acute myeloid leukemia xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable with the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced antitumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared with monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Piridinas/farmacología , Pirroles/farmacología , Sulfonamidas/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis , Proliferación Celular , Quimioterapia Combinada , Femenino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (â¼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound 27 demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound 46 (ABBV-744).
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Descubrimiento de Drogas/métodos , Piridinas/química , Piridinas/metabolismo , Pirroles/química , Pirroles/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Animales , Femenino , Células HeLa , Humanos , Ratones , Ratones SCID , Dominios Proteicos/efectos de los fármacos , Dominios Proteicos/fisiología , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Piridinas/farmacología , Pirroles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The synthesis of several pyrrolidine inhibitor analogs is described that possess nanomolar in vitro potencies against the neuraminidase enzymes expressed by the B/Memphis/3/89 and A/N1/PR/8/34 influenza strains.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Neuraminidasa/antagonistas & inhibidores , Pirrolidinas/química , Pirrolidinas/farmacología , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BILN 2061 is a macrocyclic tripeptide inhibitor of hepatitis C virus NS3-4A protease that has shown efficacy in the clinic for treating patients infected with HCV. We have synthesized a P3 aza-peptide analog of a potent macrocyclic tripeptide inhibitor closely related to BILN 2061. This aza-derivative was found to be >2 orders of magnitude less active than the parent macrocycle in both isolated enzyme (HCV NS3-4A) and HCV subgenomic replicon assays. NMR studies of P3 aza-peptides revealed these compounds adopt a beta-turn conformation stabilized by an intramolecular H-bonding interaction. Molecular models of these structures indicate a D-like configuration of the P3 aza-residue. Thus, the configurationally undefined nature at P3 in the aza-peptide allows the compound to adopt an H-bond stabilized conformation that is substantially different from that necessary for tight binding to the active site of HCV NS3 protease.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Compuestos Aza/química , Proteínas Portadoras/química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Péptidos/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Compuestos Aza/síntesis química , Compuestos Aza/farmacología , Catálisis , Péptidos y Proteínas de Señalización Intercelular , Compuestos Macrocíclicos/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/metabolismoRESUMEN
A series of gem-dialkyl naphthalenone derivatives with varied alkyl substitutions were synthesized and evaluated according to their structure-activity relationship. This investigation led to the discovery of potent inhibitors of the hepatitis C virus at low nanomolar concentrations in both enzymatic and cell-based HCV genotype 1a assays.
Asunto(s)
ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , Naftalenos/farmacología , Genotipo , Hepacivirus/genética , Relación Estructura-ActividadRESUMEN
Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Salicilamidas/síntesis química , Salicilamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Estructura Molecular , Salicilamidas/química , Relación Estructura-ActividadRESUMEN
4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-3-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b HCV NS5B polymerase. A number of these compounds exhibited potent activity against genotypes 1a and 1b HCV polymerase in both enzymatic and cell culture activities. A representative compound also showed favorable pharmacokinetics in the rat.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Área Bajo la Curva , Química Farmacéutica/métodos , Diseño de Fármacos , Genotipo , Infusiones Intravenosas , Concentración 50 Inhibidora , Modelos Químicos , Ratas , Proteínas no Estructurales Virales/genéticaRESUMEN
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Asunto(s)
Citosina/análogos & derivados , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , Estilbenos/química , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Disponibilidad Biológica , Técnicas de Química Sintética , Citosina/síntesis química , Citosina/química , Citosina/farmacocinética , Citosina/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Permeabilidad , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacocinética , Distribución Tisular , Proteínas no Estructurales Virales/químicaRESUMEN
Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.