RESUMO
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.
Assuntos
Indazóis/química , Água/química , Catálise , Indazóis/síntese química , Estrutura Molecular , Paládio/químicaRESUMO
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.
Assuntos
Catepsinas/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Catepsina L , Técnicas de Química Combinatória , Cisteína Endopeptidases , Humanos , Masculino , Estrutura Molecular , Esclerose Múltipla/tratamento farmacológico , Dor/tratamento farmacológico , Pirimidinas/sangue , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Analgésicos/uso terapêutico , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Inibidores de Cisteína Proteinase/administração & dosagem , Inibidores de Cisteína Proteinase/farmacocinética , Doenças do Sistema Nervoso Periférico/enzimologia , RatosRESUMO
An efficient two-step palladium catalysed synthesis of 2,5-disubstituted oxazoles is reported.
Assuntos
Oxazóis/síntese química , Água/química , Testes de Sensibilidade Microbiana , Mycobacterium/efeitos dos fármacos , Oxazóis/química , Oxazóis/farmacologiaRESUMO
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.
Assuntos
Analgésicos/síntese química , Encéfalo/metabolismo , Hiperalgesia/tratamento farmacológico , Naftalenos/síntese química , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Humanos , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Naftalenos/farmacocinética , Naftalenos/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Dor/tratamento farmacológico , Quinazolinas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Barreira Hematoencefálica/metabolismo , Células CHO , Células CACO-2 , Permeabilidade da Membrana Celular , Doença Crônica , Cricetinae , Cricetulus , Modelos Animais de Doenças , Humanos , Técnicas In Vitro , Camundongos , Testes para Micronúcleos , Microssomos Hepáticos/metabolismo , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Canais de Cátion TRPV/genéticaRESUMO
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.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacocinética , Administração Oral , Aminas/química , Aminoácidos/química , Disponibilidade Biológica , Ácidos Carboxílicos/química , Humanos , Estrutura Molecular , Peptídeos/administração & dosagem , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , ortoaminobenzoatos/administração & dosagem , ortoaminobenzoatos/farmacologiaRESUMO
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.