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1.
Sci Rep ; 9(1): 7742, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123329

RESUMO

Phenotypic screening in drug discovery has been revived with the expectation of providing promising lead compounds and drug targets and improving the success rate of drug approval. However, target identification remains a major bottleneck in phenotype-based drug discovery. We identified the lead compounds K542 and K405 with a selective inhibition of cell viability against sphingosine-1-phosphate lyase 1 (SGPL1)-transduced ES-2 cells by phenotypic screening. We therefore performed an in vivo pharmacological examination and observed the antitumor activity of K542 in an HT-1080 tumor-bearing mouse xenograft model. SGPL1 was expected to be a therapeutic target in some cancers, suggesting that these lead molecules might be promising candidates; however, their mechanisms of action still remain unexplained. We therefore synthesized the affinity probe Ind-tag derived from K542 and identified the proteins binding to Ind-tag via a pull-down experiment. Proteomics and biochemical analyses revealed that the target molecule of these lead compounds was Nicotinamide phosphoribosyltransferase (NAMPT). We established K542-resistant DLD-1 and HT-1080 cells, and genetic analyses of these cells identified a missense mutation in the NAMPT-encoding gene. This enzymatic experiment clearly showed that K393 exerts enzymatic inhibition against NAMPT. These proteomics, genetics and biochemical analyses clarified that compounds K542 and K405 were NAMPT inhibitors.


Assuntos
Ensaios de Seleção de Medicamentos Antitumorais/métodos , Nicotinamida Fosforribosiltransferase/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/metabolismo , Aldeído Liases/efeitos dos fármacos , Aldeído Liases/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Neoplasias/tratamento farmacológico , Fenótipo , Relação Estrutura-Atividade
2.
Urol Int ; 89(2): 162-5, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22868217

RESUMO

Bicalutamide is an anti-androgen that is used worldwide to treat prostate cancer (CaP). However, there are no data on blood bicalutamide concentrations in hemodialysis (HD) patients with CaP. Therefore, we investigated the plasma levels of bicalutamide during the peridialysis period in this population. The study group included 5 HD patients with CaP who had been treated with bicalutamide (80 mg/day) for at least 3 months. Blood samples were taken during and between HD sessions and the plasma concentrations of the active R enantiomer (R-bicalutamide) were assessed using an HPLC assay. The plasma R-bicalutamide levels on the non-dialysis day were measured in 2 patients (patients 1 and 2) immediately before dosing and 8 and 24 h after dosing. These levels were 18,730, 19,090 and 19,420 ng/ml (patient 1), and 4,522, 4,581, and 5,296 ng/ml (patient 2), respectively. The mean plasma levels of R-bicalutamide in all 5 subjects just before HD, and 2 and 4 h after the start of HD were 8,726, 9,354 and 10,068 ng/ml, respectively. These results show that bicalutamide does not accumulate and is not diluted in the blood circulation of HD patients when given at the normal dosage used in the general population.


Assuntos
Anilidas/sangue , Falência Hepática/complicações , Falência Hepática/tratamento farmacológico , Nitrilos/sangue , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Diálise Renal/métodos , Compostos de Tosil/sangue , Idoso , Anilidas/farmacocinética , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilos/farmacocinética , Estereoisomerismo , Fatores de Tempo , Compostos de Tosil/farmacocinética
3.
Opt Express ; 19(14): 13179-84, 2011 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-21747472

RESUMO

A field trial of 100-Gbit/s Ethernet over an optical transport network (OTN) is conducted using a real-time digital coherent signal processor. Error free operation with the Q-margin of 3.2 dB is confirmed at a 100 Gbit/s Ethernet analyzer by concatenating a low-density parity-check code with a OTN framer forward error correction, after 80-ch WDM transmission through 6 spans x 70 km of dispersion shifted fiber without inline-dispersion compensation. Also, the recovery time of 12 msec is observed in an optical route switching experiment, which is achieved through fast chromatic dispersion estimation functionality.


Assuntos
Redes de Comunicação de Computadores/instrumentação , Dispositivos Ópticos , Processamento de Sinais Assistido por Computador/instrumentação , Sistemas Computacionais , Desenho Assistido por Computador , Desenho de Equipamento , Análise de Falha de Equipamento , Micro-Ondas
4.
J Neuroimmunol ; 195(1-2): 73-80, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18378004

RESUMO

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), can be induced by the immunization of mice with myelin antigens in the form of myelin oligodendrocyte glycoprotein (MOG). Macrophage colony-stimulating factor (M-CSF) is required for the development of individual mononuclear phagocyte populations and is involved in the immune response. We previously reported that Ki20227 (N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-thiazole-2-yl)ethyl]urea) is a highly selective M-CSF receptor (c-fms) tyrosine kinase inhibitor. In our current study, we investigated whether Ki20227 has suppressive effects upon EAE and indeed found that this drug significantly reduced the severity of this disease both preventively and therapeutically. Notably also, Ki20227 treatments inhibited the turn-over/expansion of myeloid cells provoked by the immunization and subsequent MOG-specific T cell responses in our EAE animal model. These findings suggest that M-CSF plays a pivotal role in the development of EAE and that Ki20227 and its derivatives may be candidate drugs for the treatment of human MS.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Tiazóis/uso terapêutico , Animais , Antígenos CD/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Citometria de Fluxo/métodos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas da Mielina , Glicoproteína Associada a Mielina , Glicoproteína Mielina-Oligodendrócito , Medula Espinal/patologia , Linfócitos T/efeitos dos fármacos , Fatores de Tempo
5.
Eur J Immunol ; 38(1): 283-91, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18085662

RESUMO

Macrophage colony-stimulating factor (M-CSF) is important in the development of macrophages and osteoclasts. Previous studies have also shown that CD11b(+) myeloblasts and osteoclasts play key roles during inflammation and bone destruction in arthritic lesions. In this study, we investigated whether N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-thiazole-2-yl)ethyl] urea (Ki20227), an inhibitor of the M-CSF receptor (c-Fms), suppressed disease progression in a type II collagen (CII)-induced arthritis (CIA) mouse model. We found that Ki20227 inhibited M-CSF-dependent reactions, such as lipopolysaccharide-induced tumor necrosis factor-alpha production, which were enhanced by M-CSF in vitro. Oral administration of Ki20227 in vivo prevented inflammatory cell infiltration and bone destruction, and consequently suppressed disease progression. In addition, the number of CD11b(+), Gr-1(+), and Ly-6G(+) cells in the spleen decreased in the Ki20227-treated mice, and the CII-induced cytokine production in splenocytes isolated from the Ki20227-treated arthritic mice was also reduced. These observations indicate that Ki20227 might exert its therapeutic effects in the CIA mouse model by suppressing the M-CSF-dependent accumulation of both inflammatory and osteoclast cells, as well as by inhibiting inflammatory cytokine production. Hence, inhibitors of the c-Fms tyrosine kinase might act as anti-inflammatory or anti-osteolytic agents against arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Inflamação/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Tiazóis/uso terapêutico , Animais , Artrite Experimental/imunologia , Western Blotting , Osso e Ossos/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Progressão da Doença , Citometria de Fluxo , Fator Estimulador de Colônias de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Osteoclastos/efeitos dos fármacos , Baço/efeitos dos fármacos
6.
Mol Cancer Ther ; 5(11): 2634-43, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17121910

RESUMO

In bone metastatic lesions, osteoclasts play a key role in the development of osteolysis. Previous studies have shown that macrophage colony-stimulating factor (M-CSF) is important for the differentiation of osteoclasts. In this study, we investigated whether an inhibitor of M-CSF receptor (c-Fms) suppresses osteoclast-dependent osteolysis in bone metastatic lesions. We developed small molecule inhibitors against ligand-dependent phosphorylation of c-Fms and examined the effects of these compounds on osteolytic bone destruction in a bone metastasis model. We discovered a novel quinoline-urea derivative, Ki20227 (N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-thiazole-2-yl)ethyl]urea), which is a c-Fms tyrosine kinase inhibitor. The IC(50)s of Ki20227 to inhibit c-Fms, vascular endothelial growth factor receptor-2 (KDR), stem cell factor receptor (c-Kit), and platelet-derived growth factor receptor beta were found to be 2, 12, 451, and 217 nmol/L, respectively. Ki20227 did not inhibit other kinases tested, such as fms-like tyrosine kinase-3, epidermal growth factor receptor, or c-Src (c-src proto-oncogene product). Ki20227 was also found to inhibit the M-CSF-dependent growth of M-NFS-60 cells but not the M-CSF-independent growth of A375 human melanoma cells in vitro. Furthermore, in an osteoclast-like cell formation assay using mouse bone marrow cells, Ki20227 inhibited the development of tartrate-resistant acid phosphatase-positive osteoclast-like cells in a dose-dependent manner. In in vivo studies, oral administration of Ki20227 suppressed osteoclast-like cell accumulation and bone resorption induced by metastatic tumor cells in nude rats following intracardiac injection of A375 cells. Moreover, Ki20227 decreased the number of tartrate-resistant acid phosphatase-positive osteoclast-like cells on bone surfaces in ovariectomized (ovx) rats. These findings suggest that Ki20227 inhibits osteolytic bone destruction through the suppression of M-CSF-induced osteoclast accumulation in vivo. Therefore, Ki20227 may be a useful therapeutic agent for osteolytic disease associated with bone metastasis and other bone diseases.


Assuntos
Neoplasias Ósseas/secundário , Osteoclastos/efeitos dos fármacos , Osteólise/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Tiazóis/uso terapêutico , Fosfatase Ácida/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/metabolismo , Camundongos , Camundongos Transgênicos , Osteoclastos/patologia , Osteoclastos/fisiologia , Osteólise/metabolismo , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Endogâmicos F344 , Ratos Nus , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Fosfatase Ácida Resistente a Tartarato , Tiazóis/farmacologia
7.
Cancer Res ; 66(18): 9134-42, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16982756

RESUMO

Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor (VEGFR) tyrosine kinases. Therefore, VEGFRs are an attractive therapeutic target for cancer treatment. In the present study, we show that a quinoline-urea derivative, KRN951, is a novel tyrosine kinase inhibitor for VEGFRs with antitumor angiogenesis and antigrowth activities. KRN951 potently inhibited VEGF-induced VEGFR-2 phosphorylation in endothelial cells at in vitro subnanomolar IC50 values (IC50 = 0.16 nmol/L). It also inhibited ligand-induced phosphorylation of platelet-derived growth factor receptor-beta (PDGFR-beta) and c-Kit (IC50 = 1.72 and 1.63 nmol/L, respectively). KRN951 blocked VEGF-dependent, but not VEGF-independent, activation of mitogen-activated protein kinases and proliferation of endothelial cells. In addition, it inhibited VEGF-mediated migration of human umbilical vein endothelial cells. Following p.o. administration to athymic rats, KRN951 decreased the microvessel density within tumor xenografts and attenuated VEGFR-2 phosphorylation levels in tumor endothelium. It also displayed antitumor activity against a wide variety of human tumor xenografts, including lung, breast, colon, ovarian, pancreas, and prostate cancer. Furthermore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis revealed that a significant reduction in tumor vascular hyperpermeability was closely associated with the antitumor activity of KRN951. These findings suggest that KRN951 is a highly potent, p.o. active antiangiogenesis and antitumor agent and that DCE-MRI would be useful in detecting early responses to KRN951 in a clinical setting. KRN951 is currently in phase I clinical development for the treatment of patients with advanced cancer.


Assuntos
Antineoplásicos/farmacologia , Isoxazóis/farmacologia , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Humanos , Isoxazóis/farmacocinética , Imagem por Ressonância Magnética , Camundongos , Células NIH 3T3 , Neoplasias/enzimologia , Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Compostos de Fenilureia/farmacocinética , Fosforilação , Inibidores de Proteínas Quinases/farmacocinética , Distribuição Aleatória , Ratos , Ratos Nus , Transdução de Sinais/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Leuk Res ; 30(12): 1541-6, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16603240

RESUMO

Activating mutations of Fms-like tyrosine kinase 3 (Flt3) are the most common genetic abnormalities found in acute myeloid leukemia (AML) and represent potential therapeutic targets. The novel Flt3 inhibitor KRN383 inhibited the autophosphorylation of Flt3 bearing internal tandem duplications (ITDs) and the Asp835Tyr (D835Y) point mutation with half-maximal inhibitory concentration (IC(50)) values of < or =5.9 and 43 nM, respectively. KRN383 also inhibited the proliferation of the ITD-positive cell lines with IC(50) values of < or =2.9 nM. A single oral administration of 80 mg/kg of KRN383 eradicated ITD-positive xenograft tumors in nude mice and prolonged the survival of SCID mice carrying ITD-positive AML cells. The effectiveness of a single oral dose of KRN383 suggests that it has the potential to be used in a wide variety of clinical regimens, including multicycle and combination therapies.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Mutação Puntual , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/farmacologia , Ureia/análogos & derivados , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Administração Oral , Animais , Antimetabólitos Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Estrutura Molecular , Fosforilação , Inibidores de Proteínas Quinases/química , Taxa de Sobrevida , Fatores de Tempo , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
9.
J Med Chem ; 49(7): 2186-92, 2006 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-16570914

RESUMO

We report the structure-activity relationship of quinoline and quinazoline derivatives, which include urea, thiourea, urethane, and acylthiourea groups, as inhibitors of the platelet-derived growth factor (PDGF) receptor autophosphorylation. Our previous studies showed that the quinoline and quinazoline derivatives including urea, thiourea, and carbamate groups were highly potent compounds as the PDGF receptor autophosphorylation inhibitor, but these compounds did not exhibit receptor selectivity between the PDGF receptor and the c-kit receptor. As a result of further synthesis and biological evaluation, we have found that the quinoline and quinazoline-acylthiourea derivatives showed not only good inhibitory activity for the PDGF receptor but also receptor selectivity between the PDGF receptor and the c-kit receptor. Furthermore N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2-methylbenzoyl)thiourea exhibited potent oral efficacy in in vivo assay using the rat carotid balloon injury model. Therefore, the quinoline and quinazoline-acylthiourea derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.


Assuntos
Quinazolinas/síntese química , Quinolinas/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Tioureia/análogos & derivados , Tioureia/síntese química , Administração Oral , Animais , Estenose das Carótidas/prevenção & controle , Linhagem Celular , Masculino , Fosforilação , Proteínas Proto-Oncogênicas c-kit/metabolismo , Quinazolinas/farmacologia , Quinolinas/farmacologia , Ratos , Ratos Wistar , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Relação Estrutura-Atividade , Tioureia/farmacologia
10.
J Med Chem ; 48(5): 1359-66, 2005 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-15743179

RESUMO

N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC(50) value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRalpha and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.


Assuntos
Inibidores da Angiogênese/síntese química , Compostos de Fenilureia/síntese química , Quinolinas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Humanos , Técnicas In Vitro , Camundongos , Camundongos Nus , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Veias Umbilicais/citologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Ther Apher Dial ; 8(1): 3-32, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15128016

RESUMO

Questionnaire forms for an annual survey conducted at the end of 2001 were sent out to 3520 institutions, and 3485 replies were received (response rate, 99.00%). According to the survey, the dialysis population of Japan at year end was 219 183 patients, up 6.3% (13 049) over the year before. This equals 1721.9 dialysis patients per million population. The gross mortality rate was 9.3% for the year extending from the end of 2000 to the end of 2001. The mean age of patients beginning dialysis was 64.2 years (+/- 13.7 SD). The mean age of the overall dialysis population in the study year was 61.6 years (+/- 13.1 SD), which was also a higher age than the year before. Among dialysis patients, the primary disease was diabetic nephropathy in 38.1% of patients, slightly down from 39.1% the previous year. Chronic glomerulonephritis was the primary disease in 32.4% of cases, a decrease from 34.7% the previous year. This survey included for the first time the items of the lowest blood pressure during hemodialysis session, vasopressor therapy before dialysis and vasopressor therapy during dialysis session. An analysis of the relationship between the type of vascular access used at the initiation of dialysis and the survival prognosis revealed a significantly higher risk of death in patients undergoing dialysis with synthetic arterio-venous (AV) fistula, AV shunt, or catheter implantation into a central vein than in those receiving dialysis treatments with a native fistula. There was a significantly lower risk of death in the patient group in whom the vascular access was created at 3-6 months before initiation of dialysis than in those in whom such access was created at the time of initiation or within 3 months before the initiation of dialysis. An analysis of the risk factors affecting survival prognosis in maintenance hemodialysis patients showed that risk factors for death are post-dialysis systolic blood pressure over 180 mm Hg and lower than 120 mm Hg, blood pressure elevating progressively from the start to the end of dialysis, serum high density lipoprotein cholesterol concentration of less than 30 mg/dL, and a higher ultrafiltration rate. In comparisons of the death risk between the patient group with a history of intervention for ischemic heart disease and the patient group with a history of myocardial infarction or heart failure but without such intervention, among diabetes patients, those who underwent percutaneous transluminal coronary angioplasty had a significantly lower risk of death than those in whom no intervention was made.


Assuntos
Falência Renal Crônica/terapia , Diálise Renal/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/fisiologia , Causas de Morte , Criança , Pré-Escolar , Diabetes Mellitus/etiologia , Feminino , Humanos , Japão , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Isquemia Miocárdica/etiologia , Prognóstico , Inquéritos e Questionários , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento , Vasoconstritores/uso terapêutico
14.
Bioorg Med Chem Lett ; 14(4): 875-9, 2004 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-15012985

RESUMO

(6,7-Disubstituted-quinolin-4-yloxy-phenyl)(4-substituted-phenyl)amine derivatives were synthesized and evaluated by a cellular autophosphorylation assay for FGF-R2 in the human scirrhous gastric carcinoma cell line, OCUM-2MD3. We also performed metabolic stability studies showing that substitutions at the 7-position of quinoline affect its biological stability. In this study, we achieved a remarkable improvement in the solubility and metabolic stability of the diphenylamine derivative. The most promising compound 15e showed a significant decrease in tumor volume when orally administered.


Assuntos
Antineoplásicos/farmacologia , Difenilamina/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Administração Oral , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Difenilamina/análogos & derivados , Difenilamina/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fosforilação , Ratos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Neoplasias Gástricas/tratamento farmacológico
15.
Mol Cancer Ther ; 3(12): 1639-49, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15634658

RESUMO

Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 play a central role in angiogenesis, which is necessary for solid tumors to expand and metastasize. Specific inhibitors of VEGFR-2 tyrosine kinase are therefore thought to be useful for treating cancer. We showed that the quinazoline urea derivative KRN633 inhibited tyrosine phosphorylation of VEGFR-2 (IC50 = 1.16 nmol/L) in human umbilical vein endothelial cells. Selectivity profiling with recombinant tyrosine kinases showed that KRN633 was highly selective for VEGFR-1, -2, and -3. KRN633 also blocked the activation of mitogen-activated protein kinases by VEGF, along with human umbilical vein endothelial cell proliferation and tube formation. The propagation of various cancer cell lines in vitro was not inhibited by KRN633. However, p.o. administration of KRN633 inhibited tumor growth in several in vivo tumor xenograft models with diverse tissue origins, including lung, colon, and prostate, in athymic mice and rats. KRN633 also caused the regression of some well-established tumors and those that had regrown after the cessation of treatment. In these models, the trough serum concentration of KRN633 had a more significant effect than the maximum serum concentration on antitumor activity. KRN633 was well tolerated and had no significant effects on body weight or the general health of the animals. Histologic analysis of tumor xenografts treated with KRN633 revealed a reduction in the number of endothelial cells in non-necrotic areas and a decrease in vascular permeability. These data suggest that KRN633 might be useful in the treatment of solid tumors and other diseases that depend on pathologic angiogenesis.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Neoplasias da Próstata/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/patologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , Ratos , Ratos Nus , Transplante Heterólogo , Tirosina/metabolismo , Veias Umbilicais/efeitos dos fármacos , Veias Umbilicais/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
16.
Bioorg Med Chem ; 11(23): 5117-33, 2003 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-14604675

RESUMO

We discovered a new series of 4-phenoxyquinoline derivatives as potent and selective inhibitors of the platelet-derived growth factor receptor (PDGFr) tyrosine kinase. We researched the highly potent and selective inhibitors on the basis of both PDGFr and epidermal growth factor receptor (EGFr) inhibitory activity. First, we found a compound, Ki6783 (1), which inhibited PDGFr autophosphorylation at 0.13 microM, but it did not inhibit EGFr autophosphorylation at 100 microM. After extensive explorations, we found the two desired compounds, Ki6896 (2) and Ki6945 (3), which are substituted by benzoyl and benzamide at the 4-position of the phenoxy group on 4-phenoxyquinoline, respectively. These inhibitory activities were 0.31 and 0.050 microM, respectively, but neither of them inhibited EGFr autophosphorylation at 100 microM. We further investigated the profile of both compounds toward various tyrosine and serine/threonine kinases. The three compounds specifically inhibited PDGFr rather than the other kinases.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Animais , Inibidores Enzimáticos/síntese química , Espectroscopia de Ressonância Magnética , Camundongos , Células NIH 3T3 , Quinolinas/síntese química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
17.
Biosci Biotechnol Biochem ; 67(9): 2014-7, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14519994

RESUMO

The structural specificity of the monocarboxylic acid transporter (MCT) for the transport of phenolic acids was investigated by measuring the inhibitory effect on the fluorescein transport in Caco-2 cell monolayers. Although most of the monohydroxylated derivatives had an inhibitory effect, the di- and tri-hydroxylated ones did not. The methoxylated derivatives were more inhibitory than the hydroxylated ones in all the meta-substituted derivatives, suggesting that meta-hydroxylation of the substrate would decrease the affinity for MCT.


Assuntos
Células Epiteliais/metabolismo , Fluoresceína/farmacocinética , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacologia , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Humanos , Hidroxilação , Transportadores de Ácidos Monocarboxílicos/metabolismo , Relação Estrutura-Atividade
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