RESUMEN
Several non-benzimidazole containing inhibitors of respiratory syncytial virus are described. Core template modification, analysis of antiviral activity, physicochemistry and optimisation of properties led to the thiazole-imidazole 13, that showed a good potency and pharmacokinetic profile in the rat.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Virus Sincitiales Respiratorios/efectos de los fármacos , Animales , Antivirales/química , Bencimidazoles/química , Imidazoles/síntesis química , Imidazoles/farmacocinética , Imidazoles/farmacología , Concentración 50 Inhibidora , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
The current standard of care for hepatitis C virus (HCV)-infected patients consists of lengthy treatment with interferon and ribavirin. To increase the effectiveness of HCV therapy, future regimens will incorporate multiple direct-acting antiviral (DAA) drugs. Recently, the HCV-encoded NS5A protein has emerged as a promising DAA target. Compounds targeting NS5A exhibit remarkable potency in vitro and demonstrate early clinical promise, suggesting that NS5A inhibitors could feature in future DAA combination therapies. Since the mechanisms through which these molecules operate are unknown, we have used NS5A inhibitors as tools to investigate their modes of action. Analysis of replicon-containing cells revealed dramatic phenotypic alterations in NS5A localization following treatment with NS5A inhibitors; NS5A was redistributed from the endoplasmic reticulum to lipid droplets. The NS5A relocalization did not occur in cells treated with other classes of HCV inhibitors, and NS5A-targeting molecules did not cause similar alterations in the localization of other HCV-encoded proteins. Time course analysis of the redistribution of NS5A revealed that the transfer of protein to lipid droplets was concomitant with the onset of inhibition, as judged by the kinetic profiles for these compounds. Furthermore, analysis of the kinetic profile of inhibition for a panel of test molecules permitted the separation of compounds into different kinetic classes based on their modes of action. Results from this approach suggested that NS5A inhibitors perturbed the function of new replication complexes, rather than acting on preformed complexes. Taken together, our data reveal novel biological consequences of NS5A inhibition, which may help enable the development of future assay platforms for the identification of new and/or different NS5A inhibitors.
Asunto(s)
Antivirales/farmacología , Retículo Endoplásmico/metabolismo , Imidazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Carbamatos , Línea Celular Tumoral , Retículo Endoplásmico/ultraestructura , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatocitos/ultraestructura , Hepatocitos/virología , Humanos , Imidazoles/química , Concentración 50 Inhibidora , Lípidos , Microscopía Confocal , Modelos Moleculares , Pirrolidinas , Replicón , Bibliotecas de Moléculas Pequeñas , Valina/análogos & derivados , Proteínas no Estructurales Virales/metabolismo , Replicación ViralRESUMEN
Aldehyde oxidase (AO) is a molybdenum-containing enzyme distributed throughout the animal kingdom and capable of metabolising a wide range of aldehydes and N-heterocyclic compounds. Although metabolism by this enzyme in man is recognised to have significant clinical impact where human AO activity was not predicted by screening in preclinical species, there is very little reported literature offering real examples where drug discoverers have successfully designed away from AO oxidation. This article reports on some strategies adopted in the Pfizer TLR7 agonist programme to successfully switch off AO metabolism that was seen principally in the rat.
Asunto(s)
Aldehído Oxidasa/metabolismo , Piridinas/síntesis química , Aldehído Oxidasa/antagonistas & inhibidores , Aldehído Oxidasa/química , Animales , Células Cultivadas , Química Farmacéutica , Citosol/enzimología , Perros , Estabilidad de Medicamentos , Humanos , Masculino , Piridinas/química , Ratas , Relación Estructura-Actividad , Receptor Toll-Like 7/agonistasRESUMEN
The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Interferones/agonistas , Receptor Toll-Like 7/agonistas , Aldehído Oxidasa/metabolismo , Animales , Antivirales/química , Antivirales/farmacocinética , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Hepacivirus/fisiología , Hepatitis C/virología , Humanos , Inyecciones Intravenosas , Inductores de Interferón/síntesis química , Inductores de Interferón/química , Inductores de Interferón/farmacocinética , Inductores de Interferón/farmacología , Microsomas Hepáticos/metabolismo , Terapia Molecular Dirigida , Peso Molecular , Purinas/síntesis química , Purinas/metabolismo , Ratas , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.
Asunto(s)
Antivirales/química , Hepacivirus/efectos de los fármacos , Purinas/química , Infecciones por Virus ARN/tratamiento farmacológico , Receptor Toll-Like 7/agonistas , Administración Oral , Animales , Antivirales/síntesis química , Antivirales/uso terapéutico , Diseño de Fármacos , Ratones , Modelos Animales , Purinas/farmacocinética , Purinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Receptor Toll-Like 7/metabolismoRESUMEN
BACKGROUND: Alterations in intracellular Na+ and Ca2+ have been observed in patients with Duchenne muscular dystrophy (DMD) and in animal models of DMD, and inhibition of Na+-H+ exchanger 1 (NHE1) by rimeporide has previously demonstrated cardioprotective effects in animal models of myocardial ischemia and heart failure. Since heart failure is becoming a predominant cause of death in DMD patients, this study aimed to demonstrate a cardioprotective effect of chronic administration of rimeporide in a canine model of DMD. METHODS: Golden retriever muscular dystrophy (GRMD) dogs were randomized to orally receive rimeporide (10 mg/kg, twice a day) or placebo from 2 months to 1 year of age. Left ventricular (LV) function was assessed by conventional and advanced echocardiography. RESULTS: Compared with placebo-treated GRMD, LV function deterioration with age was limited in rimeporide-treated GRMD dogs as indicated by the preservation of LV ejection fraction as well as overall cardiac parameters different from placebo-treated dogs, as revealed by composite cardiac scores and principal component analysis. In addition, principal component analysis clustered rimeporide-treated GRMD dogs close to healthy control dogs. CONCLUSIONS: Chronic administration of the NHE1 inhibitor rimeporide exerted a protective effect against LV function decline in GRMD dogs. This study provides proof of concept to explore the cardiac effects of rimeporide in DMD patients.
Asunto(s)
Distrofia Muscular de Duchenne , Función Ventricular Izquierda , Animales , Perros , Antiarrítmicos , Modelos Animales de Enfermedad , Ecocardiografía , Corazón , Distrofia Muscular de Duchenne/tratamiento farmacológicoRESUMEN
The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.
Asunto(s)
Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Inhibidores de Fusión de VIH/química , Isoquinolinas/química , Ácidos Nicotínicos/química , Animales , Células Cultivadas , Diseño de Fármacos , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacocinética , VIH-1/efectos de los fármacos , Semivida , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Ácidos Nicotínicos/síntesis química , Ácidos Nicotínicos/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A series of piperazine derivatives were designed and synthesised as gp120-CD4 inhibitors. SAR studies led to the discovery of potent inhibitors in a cell based anti viral assay represented by compounds 9 and 28. The rat pharmacokinetic and antiviral profiles of selected compounds are also presented.
Asunto(s)
Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Inhibidores de Fusión de VIH/química , Piperazinas/química , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Diseño de Fármacos , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacocinética , VIH-1/efectos de los fármacos , Humanos , Microsomas Hepáticos/metabolismo , Piperazinas/síntesis química , Piperazinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 °C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.
RESUMEN
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phaseâ 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.
Asunto(s)
Inhibidores de Proteasas/química , Quinoxalinas/química , Valina/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacocinética , Línea Celular , Perros , Evaluación Preclínica de Medicamentos , Farmacorresistencia Viral , Semivida , Hepacivirus/metabolismo , Humanos , Microsomas Hepáticos/metabolismo , Inhibidores de Proteasas/farmacocinética , Quinoxalinas/síntesis química , Quinoxalinas/farmacocinética , Ratas , Relación Estructura-Actividad , Valina/síntesis química , Valina/química , Valina/farmacocinética , Proteínas no Estructurales Virales/metabolismoRESUMEN
In ongoing studies towards novel hepatitisâ C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.
Asunto(s)
Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Línea Celular , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Perros , Evaluación Preclínica de Medicamentos , Farmacorresistencia Viral , Hepacivirus/metabolismo , Humanos , Enlace de Hidrógeno , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
UNLABELLED: Small molecule fluorometric boron dipyrromethene probes were developed to bind hepatitis C virus-encoded NS5A protein and aid subcellular distribution studies. These molecules did not co-locate with NS5A, therefore alternative 'silent' azide reporters were used to obtain a more relevant picture of their distribution. Following pre-incubation with replicon cells, click chemistry was used to append a fluorophore to the azide that confirmed the co-localisation of the small molecule with the NS5A protein, thus providing greater insight into the antiviral mode of action of this chemotype. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12154-010-0047-1) contains supplementary material, which is available to authorized users.