RESUMO
Novel C-aryl glucoside SGLT2 inhibitors containing pyridazine motif were designed and synthesized for biological evaluation. Among the compounds tested, pyridazine containing methylthio moiety 22l or thiadiazole ring 22ah showed the best in vitro inhibitory activities in this series (IC(50)=13.4, 11.4nM, respectively) against SGLT2 to date. Subsequently, compound 22l exhibited reasonable urinary glucose excretion and glucosuria in normal SD rats, thereby demonstrating that this pyridazine series possesses both in vitro SGLT2 inhibition and in vivo efficacy, albeit to a lower degree.
Assuntos
Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Ratos , Ratos Sprague-Dawley , Transportador 2 de Glucose-SódioRESUMO
Arylpiperzine-containing pyrrole 3-carboxamide derivatives were synthesized and evaluated as novel antidepressant compounds. The various analogues were efficiently prepared and bio-assayed for binding to 5-HT(2A), 5-HT(2C) receptor, and 5-HT transporter. Based on their in vitro and in vivo activities as well as selectivity over other neurotransmitter receptors and PK profiles, 33 and 34 were identified as lead compounds. Consequently, this pyrrole series of compounds appears to be promising enough to warrant further investigation.
Assuntos
Amidas/química , Antidepressivos/química , Piperazinas/química , Pirróis/química , Inibidores Seletivos de Recaptação de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Animais , Antidepressivos/síntese química , Antidepressivos/farmacocinética , Injeções Intravenosas , Camundongos , Piperazina , Piperazinas/síntese química , Piperazinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Ratos , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine 59, 2-furan 61, and 3-thiophene 71 showed the best in vitro inhibitory activities to date (IC(50) = 3.51-7.03 nM) against SGLT2. A selected compound 61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.
Assuntos
Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Tiadiazóis/farmacologia , Animais , Nefropatias Diabéticas/tratamento farmacológico , Desenho de Fármacos , Glucosídeos/síntese química , Glucosídeos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/químicaRESUMO
Structure-activity relationship studies in a series of diarylpyrazolyl thiadiazoles identified cannabinoid-1 receptor antagonists with excellent potency and selectivity. Based on its exceptional in vivo efficacy in animal models and its favorable pharmacokinetic and toxicological profiles, 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) was selected as a preclinical candidate for the treatment of obesity.
Assuntos
Receptor CB1 de Canabinoide/antagonistas & inibidores , Tiadiazóis/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/química , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química , Tiadiazóis/farmacocinéticaRESUMO
T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC(50) of 5 microM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kappaB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRM-III reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRM-III as a potential lead compound for the treatment of T-cell-driven autoimmune diseases.
Assuntos
Proliferação de Células/efeitos dos fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Hipersensibilidade Tardia/tratamento farmacológico , Imidazóis/uso terapêutico , Fatores Imunológicos/uso terapêutico , Linfócitos T/efeitos dos fármacos , Tionas/uso terapêutico , Administração Oral , Animais , Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Hipersensibilidade Tardia/diagnóstico , Hipersensibilidade Tardia/imunologia , Imidazóis/administração & dosagem , Imidazóis/química , Imidazóis/farmacocinética , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/química , Fatores Imunológicos/farmacocinética , Interleucina-2/imunologia , Células Jurkat , Linfonodos/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Esclerose Múltipla/imunologia , Esclerose Múltipla/prevenção & controle , Fatores de Transcrição NFATC/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Índice de Gravidade de Doença , Medula Espinal/imunologia , Linfócitos T/imunologia , Tionas/administração & dosagem , Tionas/química , Tionas/farmacocinéticaRESUMO
Cannabinoid CB-1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of pentacycle derivatives. Five of the new compounds which displayed high in vitro rCB1 binding affinities were assayed for binding to hCB2 receptor. Noticeably, 2-(5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole (16l) demonstrated good binding affinity and decent selectivity for rCB1 receptor (IC(50)=1.72 nM, hCB2/rCB1=142).