RESUMEN
The efficient palladium-catalyzed synthesis of a range of substituted 2H-Indazoles via C-H arylation is reported. Reactions are performed on water and provide a direct and mild route toward 2,3-diaryl indazoles of widespread biological significance.
Asunto(s)
Indazoles/química , Agua/química , Catálisis , Indazoles/síntesis química , Estructura Molecular , Paladio/químicaRESUMEN
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Administración Oral , Animales , Encéfalo/efectos de los fármacos , Catepsina L , Técnicas Químicas Combinatorias , Cisteína Endopeptidasas , Humanos , Masculino , Estructura Molecular , Esclerosis Múltiple/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirimidinas/sangre , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.
Asunto(s)
Analgésicos/uso terapéutico , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Administración Oral , Analgésicos/administración & dosificación , Analgésicos/farmacocinética , Animales , Disponibilidad Biológica , Inhibidores de Cisteína Proteinasa/administración & dosificación , Inhibidores de Cisteína Proteinasa/farmacocinética , Enfermedades del Sistema Nervioso Periférico/enzimología , RatasRESUMEN
An efficient two-step palladium catalysed synthesis of 2,5-disubstituted oxazoles is reported.
Asunto(s)
Oxazoles/síntesis química , Agua/química , Pruebas de Sensibilidad Microbiana , Mycobacterium/efectos de los fármacos , Oxazoles/química , Oxazoles/farmacologíaRESUMEN
Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.
Asunto(s)
Analgésicos/síntesis química , Encéfalo/metabolismo , Hiperalgesia/tratamiento farmacológico , Naftalenos/síntesis química , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Humanos , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Naftalenos/farmacocinética , Naftalenos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.
Asunto(s)
Dolor/tratamiento farmacológico , Quinazolinas/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Barrera Hematoencefálica/metabolismo , Células CHO , Células CACO-2 , Permeabilidad de la Membrana Celular , Enfermedad Crónica , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Humanos , Técnicas In Vitro , Ratones , Pruebas de Micronúcleos , Microsomas Hepáticos/metabolismo , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Ratas , Solubilidad , Relación Estructura-Actividad , Canales Catiónicos TRPV/genéticaRESUMEN
The bradykinin B(1) receptor is rapidly induced after inflammation or tissue trauma and appears to play an important role in the maintenance of hyperalgesia in inflammatory conditions. Here, we describe the optimization process to identify novel, potent non-peptide human B(1) receptor antagonists based on a 2-alkylamino-5-sulfamoylbenzamide core. Optimized derivatives are selective, functional B(1) antagonists with low nanomolar affinity and exhibit oral bioavailability in animals.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacocinética , Administración Oral , Aminas/química , Aminoácidos/química , Disponibilidad Biológica , Ácidos Carboxílicos/química , Humanos , Estructura Molecular , Péptidos/administración & dosificación , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacología , ortoaminobenzoatos/administración & dosificación , ortoaminobenzoatos/farmacologíaRESUMEN
The biomimetic synthesis of a pentacyclic alkaloid (keramaphidin B, 1), an intermediate in the biogenetic pathway to the manzamine alkaloids, has been achieved. Compound 1 was formed by an intramolecular Diels-Alder reaction of macrocycle 2 in buffer followed by reduction with NaBH4 . This reaction provides the first direct expeimental evidence for the authors' biosynthetic hypothesis.