RESUMO
Inactivation of the NF-κB signaling pathway by inhibition of IKKß is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKß inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKß was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1µM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Pirimidinas/síntese química , Bibliotecas de Moléculas Pequenas/química , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Humanos , Quinase I-kappa B/química , Maleimidas/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Quinazolinas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
New potent glycogen synthase kinase-3 (GSK-3) inhibitors, 8-amino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives, were designed by modeling, synthesized and evaluated in vitro. Compound 17c showed good potency in enzyme and cell-based assays (IC50=111 nM, EC50=1.78 µM). Moreover, it has demonstrated desirable water solubility, PK profile, and moderate brain penetration.
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Triazóis/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridonas/síntese química , Piridonas/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Glycogen synthase kinase-3 (GSK-3) is emerging as a prominent therapeutic target of Alzheimer's disease (AD). A number of studies have been undertaken to develop GSK-3 inhibitors for clinical use. We report two novel GSK-3 inhibitors (C-7a and C-7b) showing good activity and pharmacokinetic (PK) profiles. IC50 of new GSK-3 inhibitors were in the range of 120-130 nM, and they effectively reduced the Aß-oligomers induced neuronal toxicity. Also, new GSK-3 inhibitors decreased the phosphorylated tau at pThr231, pSer396, pThr181, and pSer202, and inhibited the GSK-3 activity against Aß-oligomers induced neuronal cell toxicity. In B6;129-Psen1(tm1Mpm) Tg(APPSwe, tauP301L)1Lfa/Mmjax model of AD, oral administration of C-7a (20 mg/kg, 50 mg/kg) showed increased total arm entries and spontaneous alteration of Y-maze which was regarded as short-term memory. In particular, 50 mg/kg C-7a treated mice significantly decreased the level of phosphorylated tau (Ser396) in brain hippocampus. We suggest that new GSK-3 inhibitor (C-7a) is potential candidates for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Neurônios/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
A series of coumarin based TACE inhibitors were designed to bind in S1' pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1' pocket and the TACE inhibitory activity well.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Cumarínicos , Relação Quantitativa Estrutura-Atividade , Proteína ADAM17 , Animais , Benzopiranos , Sítios de Ligação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Ligação Proteica , Ratos , Eletricidade EstáticaRESUMO
Highly potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors, including 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinolin-5(6H)-one derivatives with a non-aromatic A-ring, were synthesized. Among the derivatives, 12a showed low nanomolar enzyme and cellular activity (IC(50) = 42 nM, ED(50) = 220 nM) with good water solubility. Further, 12a exhibited microsomal stability in vitro and brain permeability in vivo.
Assuntos
Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/metabolismo , Compostos Policíclicos/farmacologia , Amidas/química , Amidas/farmacocinética , Animais , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/química , Compostos Policíclicos/química , Compostos Policíclicos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
A series of coumarin types MMP inhibitors were designed based on gelastatin hydroxamates (1) and evaluated for TACE, cellular TNF-alpha, and NO inhibitory activities. Among them, compounds 9b had potent inhibitory activities in enzymatic and cellular assays and good selectivity to MMP-2 and MMP-9. Further investigation of 9b will be carried out for its efficacy in RA animal model system.
Assuntos
Cumarínicos , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Proteínas ADAM/antagonistas & inibidores , Proteína ADAM17 , Ácidos Hidroxâmicos , Inibidores de Metaloproteinases de Matriz , Óxido Nítrico/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
New thiocolchicine derivatives (1-8) were designed as less toxic anticancer agents possessing the power full anticancer activity of colchicine. The synthesis and biological evaluation of these compounds were described. As a preliminary result of biological in vitro investigation, compounds 1, 6, and 7 showed lower toxicities than that of colchicine in combination with potent anticancer activities.