RESUMEN
A synthesis of 2'-fluoro and 2'-methoxy N6-methyladenosine phosphoramidites and their successful incorporation into oligonucleotides is reported. 2'-fluoro and 2Ì-methoxy modifications of sugars in siRNAs are known to aid stability and N6-methylation modifies the potency of therapeutic silencing RNAs (siRNA). We demonstrate that a combination of those modifications incorporated into the antisense strand of siRNA leads to efficient knockdown of a target gene in cells. This work broadens the available pool of chemical modifications of therapeutic siRNAs and provides tools for their efficient synthesis.
Asunto(s)
Compuestos Organofosforados , ARN Interferente Pequeño/metabolismo , MetilaciónRESUMEN
The introduction of N6-methyladenosine (m6â A) into siRNA targeting Factor VII impacts its potency in cells and has a significant influence on the selectivity of siRNA, including reduced off-targeting. These effects are dependent on the position of m6â A in the siRNA duplex, with some of the sequences identified as more potent and/or selective than their non-methylated counterpart. These findings broaden the repertoire of available chemical modifications for siRNA therapeutics and imply potential regulatory role of N6-methyladenosine in the RNAi pathways.
Asunto(s)
Adenosina/análogos & derivados , ARN Interferente Pequeño/química , Adenosina/química , Adenosina/genética , Epigénesis Genética/genética , Conformación de Ácido Nucleico , ARN Interferente Pequeño/genéticaRESUMEN
OX1 receptor antagonists are of interest to treat, for example, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, known dual OX1/OX2 receptor antagonists are not suitable due to their sleep-inducing effects; therefore, we were interested in identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects. Herein, we describe the design of highly selective OX1 receptor antagonists driven by the X-ray structure of OX1 with suvorexant, a dual OX1/OX2 receptor antagonist. Moderately selective OX1 antagonists comprising a [2.2.1]-bicyclic scaffold served as our starting point. Based on our binding mode hypothesis, we postulated which part of the scaffold points toward one of the regions where the two binding pockets differ. Structural changes in this part resulted in a modified core with higher inherent selectivity compared to the [2.2.1]-bicyclic template. The structure-based design, synthesis, and hit-to-lead evaluation of this novel OX1 receptor-selective scaffold are discussed herein.
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Orexinas , Receptores de Orexina/metabolismoRESUMEN
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
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
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.
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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
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
Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.
Asunto(s)
Descubrimiento de Drogas , Glucocorticoides/síntesis química , Metanol/química , Receptores de Glucocorticoides/agonistas , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Artritis/tratamiento farmacológico , Sitios de Unión , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glucocorticoides/química , Glucocorticoides/farmacología , Humanos , Concentración 50 Inhibidora , Metanol/síntesis química , Metanol/farmacología , Ratones , Modelos Moleculares , Estructura Molecular , Prednisolona/química , Prednisolona/farmacología , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor BI-3231. Through high-throughput screening (HTS), using estradiol as substrate, compound 1 was identified and selected for subsequent optimization resulting in compound 45 (BI-3231). In addition to the characterization of compound 45 for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD+ dependency was investigated. To support Open Science, the chemical HSD17B13 probe BI-3231 will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.
Asunto(s)
Estudio de Asociación del Genoma Completo , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ensayos Analíticos de Alto RendimientoRESUMEN
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.
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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
A high-throughput screening campaign has identified 1,4-diazepane compounds which are potent Cannabinoid receptor 2 agonists with excellent selectivity against the Cannabinoid receptor 1. This class of compounds suffered from low metabolic stability. Following various strategies, compounds with a good stability in liver microsomes and rat PK profile have been identified.
Asunto(s)
Azepinas/farmacología , Receptor Cannabinoide CB2/agonistas , Animales , Azepinas/química , Microsomas Hepáticos/metabolismo , Ratas , Ratas WistarRESUMEN
We report a synthesis of a carbocyclic, abasic RNA phosphoramidite decorated with an amino functionality. The building block was efficiently incorporated into an RNA oligonucleotide in a site-specific manner, followed by deprotection to a free amino group. The amino moiety could be further derivatized as exemplified with fluorescein N-hydroxysuccinimide ester. Hence, this convertible building block may provide access to a variety of RNA oligonucleotides via postsynthetic amino group functionalization. In particular, providing a vector toward nucleobase replacements.
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Oligonucleótidos/síntesis química , Compuestos Organofosforados/química , ARN/síntesis química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oligonucleótidos/química , ARN/químicaRESUMEN
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.
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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
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.
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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
A high-throughput screening campaign resulted in the discovery of a highly potent dual cannabinoid receptor 1 (CB1) and 2 (CB2) agonist. Following a thorough SAR exploration, a series of selective CB2 full agonists were identified.
Asunto(s)
Receptor Cannabinoide CB2/agonistas , Estructura Molecular , Receptor Cannabinoide CB1/agonistas , 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
Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.
Asunto(s)
Huesos/efectos de los fármacos , Receptores de Glucocorticoides/agonistas , Animales , Línea Celular Tumoral , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Relación Estructura-ActividadRESUMEN
A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39.
RESUMEN
INTRODUCTION: The activation of the cannabinoid receptor 2 (CB2) affects a myriad of immune responses from inflammation to neuroprotection, demonstrates analgesic effects and suppresses responses in many animal models of pain. Questions around the involvement of CB1 activation in these effects remain, but efforts have been directed toward the discovery of highly selective CB2 modulators lacking the psychotropic effects of cannabinoids, which are mediated by the CB1 receptor. AREAS COVERED: This review covers the patent literature which was published since April 2009 on CB2 selective modulators. It provides a general summary of the CB2 biology supporting the interest in CB2 as a drug target, new potential therapeutic indications and the development status of selective CB2 agonists. EXPERT OPINION: There is a continuous interest in the CB2 receptor as a drug target. Many highly selective compounds of various chemotypes have been identified and their analgesic effects in animal models further support the potential of this mechanism in pain therapy. Several companies have initiated clinical trials. While some of these have been terminated for various reasons, one can anticipate the emergence of new drugs from CB2 modulation once a better understanding around the cannabinoid receptors is gained.
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Factores Inmunológicos/farmacología , Receptor Cannabinoide CB2/efectos de los fármacos , Animales , Diseño de Fármacos , Humanos , Factores Inmunológicos/química , Legislación de Medicamentos , Estructura Molecular , Patentes como Asunto , Receptor Cannabinoide CB2/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.