RESUMO
TYK2 is a member of the JAK family of kinases and a key mediator of IL-12, IL-23, and type I interferon signaling. These cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genetic association studies, TYK2 inhibition is an attractive therapeutic strategy for these diseases. Herein, we report the discovery of a series of highly selective catalytic site TYK2 inhibitors designed using FEP+ and structurally enabled design starting from a virtual screen hit. We highlight the structure-based optimization to identify a lead candidate 30, a potent cellular TYK2 inhibitor with excellent selectivity, pharmacokinetic properties, and in vivo efficacy in a mouse psoriasis model.
Assuntos
Psoríase , TYK2 Quinase , Animais , Humanos , Janus Quinases , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Psoríase/tratamento farmacológico , RoedoresRESUMO
Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Dislipidemias/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fígado Gorduroso/tratamento farmacológico , Pirimidinonas/farmacologia , Tiofenos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Animais , Inibidores Enzimáticos/farmacocinética , Feminino , Células Hep G2/efeitos dos fármacos , Células Hep G2/metabolismo , Humanos , Resistência à Insulina , Masculino , Simulação de Acoplamento Molecular , Obesidade/tratamento farmacológico , Obesidade/etiologia , Multimerização Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Zucker , Relação Estrutura-AtividadeRESUMO
NDI-010976, an allosteric inhibitor of acetyl-coenzyme A carboxylases (ACC) ACC1 and ACC2, reduces hepatic de novo lipogenesis (DNL) and favorably affects steatosis, inflammation, and fibrosis in animal models of fatty liver disease. This study was a randomized, double-blind, placebo-controlled, crossover trial evaluating the pharmacodynamic effects of a single oral dose of NDI-010976 on hepatic DNL in overweight and/or obese but otherwise healthy adult male subjects. Subjects were randomized to receive either NDI-010976 (20, 50, or 200 mg) or matching placebo in period 1, followed by the alternate treatment in period 2; and hepatic lipogenesis was stimulated with oral fructose administration. Fractional DNL was quantified by infusing a stable isotope tracer, [1-13 C]acetate, and monitoring 13 C incorporation into palmitate of circulating very low-density lipoprotein triglyceride. Single-dose administration of NDI-010976 was well tolerated at doses up to and including 200 mg. Fructose administration over a 10-hour period stimulated hepatic fractional DNL an average of 30.9 ± 6.7% (mean ± standard deviation) above fasting DNL values in placebo-treated subjects. Subjects administered single doses of NDI-010976 at 20, 50, or 200 mg had significant inhibition of DNL compared to placebo (mean inhibition relative to placebo was 70%, 85%, and 104%, respectively). An inverse relationship between fractional DNL and NDI-010976 exposure was observed with >90% inhibition of fractional DNL associated with plasma concentrations of NDI-010976 >4 ng/mL. CONCLUSION: ACC inhibition with a single dose of NDI-010976 is well tolerated and results in a profound dose-dependent inhibition of hepatic DNL in overweight adult male subjects. Therefore, NDI-010976 could contribute considerable value to the treatment algorithm of metabolic disorders characterized by dysregulated fatty acid metabolism, including nonalcoholic steatohepatitis. (Hepatology 2017;66:324-334).
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Lipogênese/fisiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sobrepeso/tratamento farmacológico , Acetil-CoA Carboxilase/administração & dosagem , Administração Oral , Adulto , Índice de Massa Corporal , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Medição de Risco , Resultado do TratamentoRESUMO
TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate 30, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.
Assuntos
Artrite Reumatoide , Doenças Autoimunes , Psoríase , Humanos , TYK2 Quinase , Estudo de Associação Genômica Ampla , Doenças Autoimunes/tratamento farmacológico , Psoríase/tratamento farmacológicoRESUMO
The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss-of-function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites on acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation in human liver cancer cells. Consistent with these findings, a novel, liver-specific ACC inhibitor (ND-654) that mimics the effects of ACC phosphorylation inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment.
Assuntos
Acetil-CoA Carboxilase , Carcinoma Hepatocelular/metabolismo , Lipogênese , Neoplasias Hepáticas/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/fisiologia , Animais , Células Hep G2 , Humanos , Masculino , Camundongos , Fosforilação , Ratos , Ratos WistarRESUMO
A novel series of barbituric acid derivatives were identified as selective inhibitors of alpha4beta7 MAdCAM (mucosal addressin cell adhesion molecule-1) interactions via a high throughput screening exercise. These inhibitors were optimized to submicromolar potencies in whole cell adhesion assays, retaining their selectivity over alpha4beta1 VCAM.
Assuntos
Barbitúricos/farmacologia , Adesão Celular/efeitos dos fármacos , Integrinas/antagonistas & inibidores , Mucoproteínas/antagonistas & inibidores , Animais , Barbitúricos/síntese química , Sítios de Ligação , Adesão Celular/fisiologia , Moléculas de Adesão Celular , Imunoglobulinas/metabolismo , Integrina alfa4beta1/metabolismo , Integrinas/metabolismo , Camundongos , Modelos Químicos , Mucoproteínas/metabolismo , Relação Estrutura-Atividade , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
The design, synthesis, and structure-activity relationship development of naphthalene-derived human CCR8 antagonists is described. In vitro binding assay results of these investigations are reported, critical interactions of the antagonists with CCR8 are defined, and preliminary physicochemical and pharmacokinetic data for the naphthalene scaffold are presented.
Assuntos
Naftalenos/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Sulfonamidas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Cálcio/metabolismo , Linhagem Celular , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Naftalenos/farmacocinética , Naftalenos/farmacologia , Ratos , Receptores CCR8 , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
Modeling protein-ligand interactions has been a central goal of computational chemistry for many years. We here review recent progress toward this goal, and highlight the role free energy calculation methods and computational solvent analysis techniques are now having in drug discovery. We further describe recent use of these methodologies to advance two separate drug discovery programs targeting acetyl-CoA carboxylase and tyrosine kinase 2. These examples suggest that tight integration of sophisticated chemistry teams with state-of-the-art computational methods can dramatically improve the efficiency of small molecule drug discovery.
Assuntos
Biologia Computacional/métodos , Desenho de Fármacos , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Inibidores Enzimáticos/farmacologia , Humanos , TYK2 Quinase/antagonistas & inibidoresRESUMO
Activation of CCR8 by its ligand CCL1 may play an important role in diseases such as asthma, multiple sclerosis, and cancer. The study of small molecule CCR8 antagonists will help establish the validation of these hypotheses. We report the design, synthesis, and progress toward optimization of potent small molecule CCR8 antagonists identified from a high-throughput screen. These analogues exhibit good potency in binding and chemotaxis assays, show good selectivity versus the hERG channel, and have good eADME (early absorption, distribution, metabolism, and excretion) profiles.
Assuntos
Desenho de Fármacos , Receptores de Quimiocinas/antagonistas & inibidores , Aminação , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Éter/química , Humanos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores CCR8 , Relação Estrutura-AtividadeRESUMO
Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/biossíntese , Metabolismo dos Lipídeos/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Pirimidinonas/farmacologia , Tiofenos/farmacologia , Proteínas Quinases Ativadas por AMP , Acetiltransferases/antagonistas & inibidores , Regulação Alostérica , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células/genética , Humanos , Metabolismo dos Lipídeos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The asymmetric syntheses of heteroaromatic 3-[(tert-butyldimethylsilyl)oxy]-2-azetidinones 12-16 via chiral ester enolate-imine cyclocondensation chemistry are described. The azetidinones contain heteroaromatic moieties which, in certain cases, contribute to a decrease in enantioselectivity due to possible alternate coordinations in the transition states. The (3R,4S)-3-[(tert-butyldimethylsilyl)oxy]-4-heteroaryl-2-azetidinones were subsequently converted to the heteroaromatic taxanes 31-36 and 43-45. Conformational analyses of the 3'-(2-pyridyl) analogue 31 and 3'-(2-furyl) analogue 43 indicate they have solution conformational preferences virtually identical to paclitaxel and docetaxel. Heteroaromatic N-acyl paclitaxel analogues 47-51 were prepared from N-debenzoylpaclitaxel via Schotten-Baumann acylation. The majority of the 14 analogues displayed good to excellent activity in a microtubule assembly assay in comparison to paclitaxel. The analogues were also tested for cytotoxicity against B16 melanoma cells. 3'-Dephenyl-3'-(2-pyridyl)paclitaxel (31), 3'-dephenyl-3'-(2-furyl)paclitaxel (34), N-BOC-3'-dephenyl-3'-(2-furyl)paclitaxel (43), 3'-dephenyl-3'-(2-furyl)-N-(hexanoyl)paclitaxel (44), and N-debenzoyl-N-(3-furoyl)paclitaxel (51) were found to be more cytotoxic than paclitaxel against this cell line. 3'-Dephenyl-3'-(4-pyridyl)paclitaxel (33) and N-debenzoyl-N-(2-furoyl)paclitaxel (50) displayed cytotoxicity against B16 melanoma cells similar to paclitaxel.
RESUMO
The identification, optimization, and structure-activity relationship (SAR) of small-molecule CCR4 antagonists is described. An initial screening hit with micromolar potency was identified that was optimized to sub-micromolar binding potency by enantiomer resolution, halogenation of the naphthalene ring, and extension of the alkyl chain linker between the central piperidine ring and the terminal aryl group. An antagonist was identified that showed good cross-reactivity against the mouse receptor and inhibited CCR4-based cell recruitment in dose-dependent fashion.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Naftalenos/química , Naftalenos/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Camundongos , Camundongos Endogâmicos BALB C , Naftalenos/síntese química , Receptores CCR4 , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
OBJECTIVE: The NF-kappaB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-kappaB activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody-induced arthritis. METHODS: ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-kappaB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints. RESULTS: Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-kappaB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-kappaB pathway, i.e., KC, epithelial neutrophil-activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor alpha, interleukin-1beta, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints. CONCLUSION: Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.
Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Carbolinas/farmacologia , Inibidores Enzimáticos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Niacinamida/análogos & derivados , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Administração Oral , Animais , Artrite Experimental/enzimologia , Artrite Experimental/patologia , Artrite Reumatoide/enzimologia , Artrite Reumatoide/patologia , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica/efeitos dos fármacos , Quinase I-kappa B/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Articulações/patologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , NF-kappa B/metabolismo , Niacinamida/farmacologia , RNA Mensageiro/metabolismo , Espectrometria de Fluorescência/métodos , Regulação para Cima/efeitos dos fármacosRESUMO
IkappaB kinase (IKK) beta is essential for inflammatory cytokine-induced activation of nuclear factor kappaB (NF-kappaB). NF-kappaB plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKKbeta inhibitor N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a beta-carboline derivative, on NF-kappaB signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKKbeta with an IC50 of 60 nM when evaluated in an IkappaBalpha kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration-dependently inhibits tumor necrosis factor alpha (TNFalpha)-stimulated NF-kappaB signaling via inhibition of IkappaBalpha phosphorylation, degradation, and NF-kappaB translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNFalpha- or interleukin (IL)-1beta-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKKbeta-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide- or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKKbeta-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1beta-induced matrix metalloproteinase production with an IC50 of approximately 1 microM. ML120B also blocked IL-1beta-induced prostaglandin E2 production. In summary, ML120B blocked numerous NF-kappaB-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKKbeta inhibitors as anti-inflammatory agents for the treatment of RA.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Células do Tecido Conjuntivo , Inibidores Enzimáticos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Condrócitos/efeitos dos fármacos , Condrócitos/enzimologia , Condrócitos/imunologia , Células do Tecido Conjuntivo/efeitos dos fármacos , Células do Tecido Conjuntivo/enzimologia , Células do Tecido Conjuntivo/imunologia , Citocinas/imunologia , Dinoprostona/imunologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Fibroblastos/imunologia , Células HeLa , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/enzimologia , Mastócitos/imunologia , Estrutura Molecular , NF-kappa B/imunologia , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/citologiaRESUMO
OBJECTIVE: The IKK complex regulates NF-kappaB activation, an important pathway implicated in the rheumatoid arthritis (RA) disease process. This study was undertaken to assess the efficacy of N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a potent and selective small molecule inhibitor of IKKbeta. METHODS: Polyarthritis was induced in rats by injection of Freund's complete adjuvant into the hind footpad. ML120B was administered orally twice daily, either prophylactically or therapeutically. Paw volumes and body weights were measured every 2-3 days throughout the study. We assessed bone erosions by several methods: histologic evaluation, quantitative micro-computed tomography (micro-CT) imaging analysis, and measurement of type I collagen fragments in the serum. Quantitative polymerase chain reaction was used to evaluate expression of messenger RNA for genes related to inflammation and to bone and cartilage integrity. RESULTS: Oral administration of ML120B inhibited paw swelling in a dose-dependent manner (median effective dosage 12 mg/kg twice daily) and offered significant protection against arthritis-induced weight loss as well as cartilage and bone erosion. We were able to directly demonstrate that NF-kappaB activity in arthritic joints was reduced after ML120B administration. Also, we observed that down-regulation of the NF-kappaB pathway via IKKbeta inhibition dampened the chronic inflammatory process associated with rat adjuvant-induced arthritis. CONCLUSION: The results of the present study suggest that IKKbeta inhibition is an effective therapeutic approach to treat both the inflammation and the bone/cartilage destruction observed in RA. Methods for the determination of serum markers for bone and cartilage destruction, as well as micro-CT analysis, may aid in predicting and evaluating the therapeutic efficacy of IKKbeta inhibition therapy in humans.
Assuntos
Artrite Reumatoide/fisiopatologia , Osso e Ossos/patologia , Cartilagem/patologia , Quinase I-kappa B/antagonistas & inibidores , Animais , Artrite Experimental , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Osso e Ossos/metabolismo , Carbolinas/farmacologia , Cartilagem/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Adjuvante de Freund , Regulação da Expressão Gênica , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Ratos , Ratos Endogâmicos Lew , Fator de Necrose Tumoral alfa/metabolismoRESUMO
[reaction: see text] Reaction of o-azidobenzenesulfonamides with polymer-supported triphenylphosphine affords the corresponding iminophosphoranes. Subsequent reaction with isocyanates gives 3-amino-1,2,4-benzothiadiazine 1,1-dioxides in high yields and purities. The reaction has been successfully applied to the synthesis of derivatives with various substituents at the 2- and 3-positions and in the benzenoid ring.