RESUMEN
We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas/química , Animales , Antivirales/química , Carbamatos/química , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral/genética , Guanidinas/química , Hepacivirus/enzimología , Hepacivirus/genética , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ácido Oxámico/química , Ratas , Inhibidores de Serina Proteinasa/química , Relación Estructura-Actividad , Urea/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
Asunto(s)
Antivirales/síntesis química , Farmacorresistencia Viral , Hepacivirus/efectos de los fármacos , Inhibidores de Serina Proteinasa/síntesis química , Urea/análogos & derivados , Urea/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Hepacivirus/enzimología , Hepacivirus/genética , Interacciones Hidrofóbicas e Hidrofílicas , Hígado/metabolismo , Mutación , Ratas , Replicón/efectos de los fármacos , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad , Urea/farmacocinética , Urea/farmacología , Proteínas no Estructurales Virales/genéticaRESUMEN
We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.
Asunto(s)
Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.
Asunto(s)
Compuestos de Boro/química , Hepacivirus/enzimología , Inhibidores de Proteasas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Animales , Compuestos de Boro/síntesis química , Compuestos de Boro/farmacocinética , Dominio Catalítico , Hepacivirus/efectos de los fármacos , Masculino , Modelos Moleculares , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Replicación Viral/efectos de los fármacosRESUMEN
Key binding interactions of the anthranilimide based glycogen phosphorylase a (GPa) inhibitor 2 from X-ray crystallography studies are described. This series of compounds bind to the AMP site of GP. Using the binding information the core and the phenyl urea moieties were optimized. This work culminated in the identification of compounds with single nanomolar potency as well as in vivo efficacy in a diabetic model.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucógeno Fosforilasa/antagonistas & inhibidores , Hipoglucemiantes/síntesis química , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología , Animales , Glucemia/análisis , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Hipoglucemiantes/sangre , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ratones , Conformación Molecular , Estructura Molecular , Relación Estructura-Actividad , Urea/farmacología , ortoaminobenzoatos/sangre , ortoaminobenzoatos/químicaRESUMEN
Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Pirimidinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Tiofenos/síntesis química , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Sitios de Unión , Células CHO , Cricetinae , Cricetulus , Ratones , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Receptores de Somatostatina/química , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.
Asunto(s)
Bencimidazoles/farmacología , Obesidad/tratamiento farmacológico , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Bencimidazoles/farmacocinética , Disponibilidad Biológica , Composición Corporal , Relación Dosis-Respuesta a Droga , Ratones , Modelos Animales , Relación Estructura-Actividad , Pérdida de Peso/efectos de los fármacosRESUMEN
Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented.