RESUMO
A novel series of arylsulfonylaminomethyl-3-(1-phenyl-5-isopropyl)pyrazoles was evaluated for serotonin receptor subtype 6 (5-HT6R) antagonistic effects in vitro. We also investigated their neuropathic pain-alleviating effects in vivo using a rat spinal nerve ligation (SNL) model. Bicyclic aromatic sulfonamino groups, such as naphthalene and quinolin-substituted derivatives, showed good 5-HT6 inhibitory activity in vitro. Among them, selected compounds, 12 and 13, having 8-quinoylsulfonamino groups, showed potent neuropathic pain-alleviating effects in the rat model.
Assuntos
Inibidores Enzimáticos/farmacologia , Neuralgia/tratamento farmacológico , Pirazóis/farmacologia , Receptores de Serotonina/metabolismo , Nervos Espinhais/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Estrutura Molecular , Neuralgia/patologia , Pirazóis/química , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/patologia , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
A novel series of fused-benzensulfonamide 2-N-(pyrazol-3-yl)methylbenzo[d]isothiazole-1,1-dioxide derivatives was designed and synthesized as metabolically stable T-type calcium channel inhibitors. Several compounds, 9, 10, and 17, displayed potent T-type channel inhibitory activity. Among them, compounds 10 and 17 showed good metabolic stability in human liver microsomes, and low hERG channel and CYP450 inhibition. Compound 10 exhibited diabetic neuropathic pain-alleviating effects in a streptozotocin-induced peripheral diabetic neuropathy (PDN) model. The maximum efficacy of compound 10, which was 3-fold more potent than gabapentin, was observed at 1h after administration, and co-administration of compound 10 with gabapentin showed a considerable synergic effect.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Tiazóis/química , Animais , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/química , Canais de Cálcio Tipo T/metabolismo , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Meia-Vida , Humanos , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/metabolismo , Neuralgia/etiologia , Neuralgia/prevenção & controle , Pirazóis/química , Ratos , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/uso terapêuticoRESUMO
A novel series of 3-arylsulfonylamino-5,6-dihydro-6-substituted-1H-pyrazolo[3,4-c]pyridine-7-ones was designed and synthesized as 5-HT6 ligands. Among the derivatives synthesized, the lead compound, 12b, having piperidine functionality at the 6-position and (1-naphthyl)sulfonamino at the 3-position of the core structure showed the most potent 5-HT6 inhibitory activity in vitro, good stability without CYP liability, and good neuropathic pain alleviation activity in a rat animal model.
