RESUMEN
Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/química , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Oxadiazoles/química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/metabolismo , Proteínas Activadoras de la 5-Lipooxigenasa/química , Animales , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/metabolismo , Semivida , Humanos , Concentración 50 Inhibidora , Masculino , Microsomas Hepáticos/metabolismo , Oxadiazoles/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Solubilidad , Relación Estructura-ActividadRESUMEN
The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.
Asunto(s)
Acetamidas/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Descubrimiento de Drogas , Inhibidores de la Lipooxigenasa/farmacología , Oxadiazoles/farmacología , Acetamidas/síntesis química , Acetamidas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Modelos Moleculares , Conformación Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-ActividadRESUMEN
Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.
Asunto(s)
Isoxazoles/química , Prolina/química , Ácido Pirrolidona Carboxílico/análogos & derivados , Receptor Cannabinoide CB2/agonistas , Animales , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/tratamiento farmacológico , Semivida , Humanos , Isoxazoles/farmacocinética , Isoxazoles/uso terapéutico , Ligandos , Masculino , Microsomas Hepáticos/metabolismo , Prolina/farmacocinética , Prolina/uso terapéutico , Unión Proteica , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/farmacocinética , Ácido Pirrolidona Carboxílico/uso terapéutico , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
Computer-aided drug design scaffold hopping strategies were utilized to identify new classes of CB2 agonists when compounds of an established series with low nanomolar potency were challenging to optimize for good drug-like properties. Use of ligand-based design strategies through BI Builder (a tool for de novo design) and PharmShape (a virtual screening software package) approaches led to the discovery of new chemotypes. Specifically, compounds containing azetidine-, proline-, and piperidine-based cores were found to have low nanomolar and picomolar CB2 agonist activities with drug-like properties considered appropriate for early profiling.
Asunto(s)
Diseño de Fármacos , Receptor Cannabinoide CB2/agonistas , Diseño Asistido por Computadora , Humanos , Ligandos , Microsomas Hepáticos/metabolismo , Unión Proteica , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.
Asunto(s)
Ácidos Pipecólicos/química , Piperidinas/química , Receptor Cannabinoide CB2/agonistas , Tiazinas/química , Animales , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/tratamiento farmacológico , Semivida , Humanos , Ligandos , Masculino , Microsomas Hepáticos/metabolismo , Dolor/tratamiento farmacológico , Ácidos Pipecólicos/farmacocinética , Ácidos Pipecólicos/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Unión Proteica , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Solubilidad , Relación Estructura-Actividad , Tiazinas/farmacocinética , Tiazinas/uso terapéuticoRESUMEN
A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability.
Asunto(s)
Azepinas/química , Receptor Cannabinoide CB2/agonistas , Azepinas/farmacología , Células CACO-2 , Permeabilidad de la Membrana Celular , Ensayos Analíticos de Alto Rendimiento , Humanos , Microsomas Hepáticos/metabolismo , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described.
Asunto(s)
Bencimidazoles/síntesis química , Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Bencimidazoles/farmacología , Complejo CD3/biosíntesis , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Identification and optimization of two classes of CB2 selective agonists are described. A representative from each class is profiled in a murine model of inflammation and each shows similar efficacy to prednisolone upon oral dosing.
Asunto(s)
Morfolinas/síntesis química , Receptor Cannabinoide CB2/agonistas , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Línea Celular , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Inflamación , Ratones , Modelos Químicos , Estructura Molecular , Morfolinas/farmacología , Receptor Cannabinoide CB2/química , EstereoisomerismoRESUMEN
A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays.
Asunto(s)
Glucocorticoides/agonistas , Ligandos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
We report on the nuclear receptor binding affinities, cellular activities of transrepression and transactivation, and anti-inflammatory properties of a quinol-4-one and other A-ring mimetic containing nonsteroidal class of glucocorticoid agonists.