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1.
Chimia (Aarau) ; 73(7): 581-590, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31431218

RESUMO

The macrolide rapamycin ( 1 ) was first described as an antifungal agent in 1975. Even though its biological target and the molecular details were yet to be discovered, rapamycin attracted our interest in the early 90s based on its reported immunosuppressive activity in transplantation models and based on findings that its mechanism of action was different from those of the known immunosuppressive agents ciclosporin and FK506. In this review we describe our efforts to chemically modify this complex and chemically very sensitive natural product. Despite the limitations regarding the reaction conditions compatible with rapamycin we discovered ways of selectively modifying specific functional groups. This allowed us, among others, to improve the stability of the parent molecule towards ring-opening. Our efforts culminated in the discovery and development of the 40-O-alkylated derivative everolimus 2 which became a useful drug in solid organ transplantation, in various cancer indications and as the active principle of the market leading drug-eluting stent.


Assuntos
Sirolimo/química , Produtos Biológicos , Stents Farmacológicos , Everolimo , Imunossupressores
2.
Bioorg Med Chem Lett ; 27(4): 781-786, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28131714
3.
Bioorg Med Chem Lett ; 24(20): 4812-7, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25248678

RESUMO

A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results led to the consideration of topical delivery of these molecules, and to the identification of a lead molecule 7 which shows promising PK and PD in a murine model of pulmonary hypertension after intra-tracheal dosing.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismo
4.
Bioorg Med Chem Lett ; 21(24): 7367-72, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22078216

RESUMO

The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes δ, ε, η, θ (in particular PKCε/η, and display a 10-100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCθ-dependent pathways in vitro and in vivo. In vitro, a-CD3/a-CD28-induced lymphocyte proliferation could be effectively blocked in 10% rat whole blood. In mice, 11 dose-dependently inhibited Staphylococcus aureus enterotoxin B-triggered IL-2 serum levels after oral dosing.


Assuntos
Naftiridinas/química , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Administração Oral , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Enterotoxinas/toxicidade , Interleucina-2/sangue , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Naftiridinas/síntese química , Naftiridinas/farmacocinética , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Ratos , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
5.
Cancer Res ; 71(7): 2643-53, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21324920

RESUMO

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. The ABC subtype of DLBCL is associated with constitutive activation of the NF-κB pathway, and oncogenic lesions have been identified in its regulators, including CARD11/CARMA1 (caspase recruitment domain-containing protein 11), A20/TNFAIP3, and CD79A/B. In this study, we offer evidence of therapeutic potential for the selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in preclinical models of DLBCL. A significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to STN, and we found that the molecular nature of NF-κB pathway lesions predicted responsiveness. CD79A/B mutations correlated with STN sensitivity, whereas CARD11 mutations rendered ABC DLBCL cell lines insensitive. Growth inhibitory effects of PKC inhibition correlated with NF-κB pathway inhibition and were mediated by induction of G1-phase cell-cycle arrest and/or cell death. We found that STN produced significant antitumor effects in a mouse xenograft model of CD79A/B-mutated DLBCL. Collectively, our findings offer a strong rationale for the clinical evaluation of STN in ABC DLBCL patients who harbor CD79 mutations also illustrating the necessity to stratify DLBCL patients according to their genetic abnormalities.


Assuntos
Antígenos CD79/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Quinazolinas/farmacologia , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fase G1/efeitos dos fármacos , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/enzimologia , Camundongos , Mutação , NF-kappa B/metabolismo , Proteína Quinase C/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcr/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Drug Metab Dispos ; 36(8): 1457-60, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18448571

RESUMO

The immunosuppressant macrolide everolimus was found to be metabolized in animals and humans to a phosphocholine ester (ATG181), a hitherto unknown type of conjugate in xenobiotic metabolism. The structure of ATG181 was elucidated by mass spectrometry and confirmed by synthesis. ATG181 was among the most prominent metabolites of everolimus in rat, monkey, and human blood and was found also in various tissues of the rat, whereas no ATG181 was identified in the urine and feces of the species investigated. The metabolite showed binding to FK506 binding protein with a 2- to 3-fold higher affinity than everolimus. However, ATG181 exhibited only marginal in vitro immunosuppressive activity and is therefore very unlikely to contribute in a relevant manner to the immunosuppressive effect of everolimus.


Assuntos
Imunossupressores/farmacologia , Fosforilcolina/metabolismo , Sirolimo/análogos & derivados , Animais , Cromatografia Líquida , Ésteres , Everolimo , Humanos , Imunossupressores/metabolismo , Teste de Cultura Mista de Linfócitos , Masculino , Espectrometria de Massas , Ratos , Ratos Wistar , Sirolimo/metabolismo , Sirolimo/farmacologia
7.
AJR Am J Roentgenol ; 184(5): 1420-6, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15855089

RESUMO

OBJECTIVE: Our objective was to assess and compare the patterns of late enhancement (LE) in contrast-enhanced cardiac MRI caused by myocardial infarction and different myocardial diseases that are not related to ischemic infarction. MATERIALS AND METHODS: A total of 811 consecutive contrast-enhanced cardiac MRI studies performed for different indications were reviewed for left ventricular myocardial LE after gadopentetate dimeglumine administration. MRI studies were performed on a 1.5-T scanner using an inversion recovery turbo FLASH sequence (TR/TE, 8/4 msec; flip angle, 25 degrees). The LE pattern of ischemic infarction scar was compared with that in nonischemic myocardial disease. RESULTS: LE was found in 421 (52%) patients. In all patients with myocardial infarction, LE included the subendocardial layer. Nineteen patients without history of myocardial infarction and angiographically excluded coronary artery disease showed different patterns of LE caused by myocarditis, sarcoidosis, arrhythmogenic right ventricular dysplasia, cardiomyopathy, endomyocardial fibrosis, and iatrogenic scars after biopsy, ablation of septal hypertrophy, and myocardial laser revascularization. CONCLUSION: LE in contrast-enhanced cardiac MRI is not specific for ischemic infarction. LE in ischemic infarction always involves the subendocardial layer, whereas it does not necessarily do so in other myocardial diseases. Therefore, if LE omit the subendocardial layer, different nonischemic myocardial diseases have to be considered. The pattern of LE might be helpful for the differential diagnosis of myocardial disease and in distinguishing it from ischemic disease.


Assuntos
Meios de Contraste , Gadolínio DTPA , Cardiopatias/patologia , Aumento da Imagem , Imageamento por Ressonância Magnética , Infarto do Miocárdio/patologia , Adulto , Idoso , Cicatriz/patologia , Diagnóstico Diferencial , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade
8.
J Med Chem ; 47(20): 4950-7, 2004 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-15369399

RESUMO

One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Macrolídeos/química , Macrolídeos/farmacologia , Tacrolimo/análogos & derivados , Tacrolimo/química , Tacrolimo/farmacologia , Administração por Inalação , Animais , Anti-Inflamatórios/administração & dosagem , Área Sob a Curva , Bioquímica/métodos , Células Cultivadas , Desenho de Fármacos , Eosinófilos/efeitos dos fármacos , Meia-Vida , Humanos , Macaca mulatta , Macrolídeos/administração & dosagem , Ratos , Ratos Endogâmicos BN , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
9.
Transplantation ; 77(6): 914-20, 2004 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-15077037

RESUMO

BACKGROUND: This study assesses the safety and efficacy of the novel human anti-human CD154 monoclonal antibody ABI793 in rhesus monkeys. METHODS: Outbred rhesus monkeys were used for renal transplantation from major histocompatibility complex-mismatched donors. Seven recipients were treated with ABI793, and six untreated recipients were used as controls. Graft function was monitored by urine output, serum creatinine, and renal biopsy. Phenotypic analysis of peripheral blood lymphocytes and mixed lymphocyte reaction were performed before transplantation and periodically after transplantation. Anti-donor major histocompatibility complex class I antibody levels were measured at the time of sacrifice. RESULTS: Monkeys in the treated group demonstrated prolonged graft survival compared with controls. One monkey was sacrificed because of a urine leak on postoperative day 13. Three monkeys were sacrificed because of acute rejection (days 44, 149, and 158). Two monkeys were sacrificed because of chronic active rejection (days 154 and 221). One monkey was sacrificed on day 139 without rejection to observe the effects of ABI793 in the absence of rejection. There were no obvious clinical side effects of ABI793, but microscopic thromboembolic changes were observed in two monkeys. Lymphocyte subsets remained unaltered in all monkeys. Mixed lymphocyte reaction showed nonspecific suppression 6 weeks after transplantation. The monkeys with chronic active rejection showed relatively strong alloantibody responses. CONCLUSIONS: ABI793 induces prolonged renal allograft survival in rhesus monkeys. Nevertheless, thromboembolic complications may occur and chronic allograft nephropathy may develop after anti-CD154 treatment is discontinued.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Ligante de CD40/imunologia , Ligante de CD40/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Rim/fisiologia , Animais , Anticorpos Monoclonais Humanizados , Creatinina/sangue , Diurese , Teste de Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Transplante de Rim/patologia , Teste de Cultura Mista de Linfócitos , Macaca mulatta , Fatores de Tempo , Transplante Homólogo
10.
Transplantation ; 77(5): 717-26, 2004 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15021835

RESUMO

BACKGROUND: Anti-CD154 monoclonal antibodies (mAbs) cause long-term graft survival in preclinical allotransplantation experiments. This is the first report on the efficacy and safety of ABI793, a novel human anti-human CD154 mAb, in Cynomolgus renal transplant recipients. METHODS: ABI793 (human immunoglobulin-G1:kappa) was derived from a hybridoma generated after immunization of human immunoglobulin transgenic mice (HuMAb-Mouse, Medarex Inc., Annandale, NJ). Cynomolgus monkey recipients of major histocompatibility complex-mismatched, life-supporting renal allografts were treated repeatedly with intravenous ABI793 for a 3-month period posttransplantation. Graft function was monitored by serum creatinine, and rejection was confirmed histologically. RESULTS: ABI793 binds to human, Cynomolgus and Rhesus monkey CD154; it inhibits dose dependently in vitro CD154:CD40 binding and human mixed lymphocyte reaction. ABI793 is comparable to the mouse anti-human CD154 mAbs 5c8 and 24-31 with respect to affinity, inhibitory capacity, and species specificity; however, ABI793 binds to a different CD154 epitope. With 20 mg/kg of ABI793, five of nine recipients showed substantially prolonged graft survival after cessation of treatment, whereas four of nine recipients were killed because of high serum creatinine while still receiving treatment. ABI793 treatment was associated with episodes of severe acute tubular necrosis (which was unrelated to rejection and responded to fluid and diuretic treatment) and a decrease in platelet numbers. Chronic and acute thromboembolic vascular lesions with hemorrhages were observed in the lung and brain of two allograft recipients. None of these side effects were observed in animals that underwent autotransplantation, thus excluding direct toxicity of ABI793. CONCLUSIONS: ABI793 treatment effectively prevents graft rejection in Cynomolgus monkeys. Evidence for rare thromboembolic events, as also previously observed with different anti-human CD154 mAbs, suggests that thromboembolic complications may be a class effect of anti-CD154 mAbs, unrelated to their epitope specificity.


Assuntos
Anticorpos Monoclonais/farmacologia , Ligante de CD40/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/imunologia , Animais , Especificidade de Anticorpos , Linhagem Celular , Epitopos/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Rim/citologia , Macaca fascicularis , Camundongos , Camundongos Transgênicos , Transplante Autólogo , Transplante Homólogo
11.
Transplantation ; 75(10): 1710-7, 2003 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-12777861

RESUMO

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) represent a life-threatening complication of standard immunosuppressive therapy. The impact of novel, rapamycin-related immunosuppressive drugs on the pathogenesis of PTLDs remains undefined. METHODS: We tested the effect of everolimus (RAD, Novartis Pharma AG, Basel, Switzerland) on human PTLD-derived cells using in vitro assays and an in vivo severe combined immunodeficiency disease mouse xenotransplant model. RESULTS: Everolimus profoundly inhibited the proliferation, cell-cycle progression, and survival of the PTLD-1 cell line established from a pulmonary PTLD. Equally profound inhibition of PTLD-1 growth was achieved in vivo at well-tolerated everolimus doses of 0.5 to 5 mg/kg per day. Five mg/kg per day of everolimus, given once per day, inhibited PTLD-1 tumor volume gain by more than 10-fold in treated mice compared with untreated mice. Because the subsequent pharmacokinetic analysis indicated rapid everolimus absorption, distribution, and clearance in mice (with a half-life of 3 to 6 hr and maximum drug blood concentration reached after 0.5 to 1 hr), treatment was changed to a twice-daily regimen. Everolimus given twice daily at 0.5 mg/kg per dose inhibited tumor-volume gain by more than 60-fold and at 0.25 mg/kg per dose by more than 10-fold. Similar everolimus doses were required to prevent graft rejection in a mouse heart allotransplantation model; the highest dose tested (1.5 mg/kg twice daily) resulted in long-term graft survival in all mice that underwent transplantation. CONCLUSIONS: Everolimus displays a potent inhibitory effect on PTLD-derived cells in vitro and in vivo in a dose range leading to prevention of allograft rejection and may prove effective in both the prevention and treatment of PTLDs in transplant patients.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Coração/efeitos adversos , Imunossupressores/administração & dosagem , Transplante de Fígado/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/patologia , Inibidores de Proteínas Quinases , Proteínas Quinases , Sirolimo/administração & dosagem , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transplante de Células , Relação Dose-Resposta a Droga , Everolimo , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos , Camundongos SCID , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR , Transplante Heterólogo
12.
AJR Am J Roentgenol ; 179(6): 1539-44, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12438051

RESUMO

OBJECTIVE: The aim of our study was to compare the diagnostic accuracy achieved using different MR techniques with the diagnostic accuracy achieved using transthoracic and transesophageal echocardiography to detect intracardiac thrombi. MATERIALS AND METHODS: Twenty-four patients with known or suspected intracardiac thrombi were examined using MR imaging and echocardiography. All MR examinations were performed on a 1.5-T MR scanner using dark-blood-prepared half-Fourier acquisition single-shot turbo spin-echo (HASTE) sequences, fast imaging steady-state free precession (trueFISP) cine sequences, and inversion recovery gradient-echo fast low-angle-shot (inversion recovery turbo FLASH) sequences after injection of 0.2 mmol/kg of gadolinium diethylene triamine pentaacetic acid. RESULTS: MR imaging and echocardiography revealed 12 thrombi-two in the right atrium, one in the right ventricle, three in the left atrium, and six in the left ventricle. Compared with echocardiography, MR imaging revealed three additional thrombi in the left ventricle; these thrombi were confirmed at surgery. All 15 thrombi appeared as filling defects on early contrast-enhanced inversion recovery turbo FLASH MR images. Only seven thrombi were detected on HASTE images, and 10 thrombi were seen on trueFISP images. Four thrombi showed enhancement 10-20 min after contrast material injection and were characterized as organized clots. CONCLUSION: Contrast-enhanced inversion recovery turbo FLASH sequences were superior to dark-blood-prepared HASTE and trueFISP cine MR images in revealing intracardiac thrombi. Compared with transthoracic echocardiography, MR imaging was more sensitive for the detection of left ventricular thrombi. The characterization of thrombi may be used to predict the risk of embolism, which is higher for subacute clots than for organized thrombi.


Assuntos
Cardiopatias/diagnóstico , Imageamento por Ressonância Magnética , Trombose/diagnóstico , Adulto , Idoso , Meios de Contraste , Ecocardiografia , Feminino , Gadolínio DTPA , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Cardiopatias/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/diagnóstico por imagem
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