Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 21(1): 484-7, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21126875

RESUMO

A novel series of EP(4) ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic and pharmacological profiles of these compounds was explored. It was found that these compounds show good pharmacokinetics in rat and are efficacious in pre-clinical models of pain and inflammation.


Assuntos
Indóis/química , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indóis/farmacocinética , Indóis/uso terapêutico , Ligantes , Ratos , Receptores de Prostaglandina E Subtipo EP2/agonistas , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 21(11): 3471-4, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21515053

RESUMO

A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified.


Assuntos
Amidas/síntese química , Amidas/farmacologia , Indóis/síntese química , Indóis/farmacologia , Receptores de Dopamina D2/agonistas , Amidas/química , Animais , Indóis/química , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Ratos
3.
Bioorg Med Chem Lett ; 21(3): 1041-6, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21215624

RESUMO

Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.


Assuntos
Amidas/química , Indóis/química , Naftalenos/química , Quinolinas/química , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Compostos de Sulfonilureia/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/síntese química , Indóis/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/farmacocinética
4.
Bioorg Med Chem Lett ; 21(1): 288-93, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21106375

RESUMO

In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed.


Assuntos
Carbolinas/química , Pneumopatias/tratamento farmacológico , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Carbolinas/farmacocinética , Carbolinas/uso terapêutico , Humanos , Macaca mulatta , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-Atividade
5.
J Exp Med ; 199(2): 199-207, 2004 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-14718517

RESUMO

A rodent model of sepsis was used to establish the relationship between caspase inhibition and inhibition of apoptotic cell death in vivo. In this model, thymocyte cell death was blocked by Bcl-2 transgene, indicating that apoptosis was predominantly dependent on the mitochondrial pathway that culminates in caspase-3 activation. Caspase inhibitors, including the selective caspase-3 inhibitor M867, were able to block apoptotic manifestations both in vitro and in vivo but with strikingly different efficacy for different cell death markers. Inhibition of DNA fragmentation required substantially higher levels of caspase-3 attenuation than that required for blockade of other apoptotic events such as spectrin proteolysis and phosphatidylserine externalization. These data indicate a direct relationship between caspase inhibition and some apoptotic manifestations but that small quantities of uninhibited caspase-3 suffice to initiate genomic DNA breakdown, presumably through the escape of catalytic quantities of caspase-activated DNase. These findings suggest that putative caspase-independent apoptosis may be overestimated in some systems since blockade of spectrin proteolysis and other cell death markers does not accurately reflect the high degrees of caspase-3 inhibition needed to prevent DNA fragmentation. Furthermore, this requirement presents substantial therapeutic challenges owing to the need for persistent and complete caspase blockade.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Oxidiazóis/farmacologia , Pirazinas/farmacologia , Sepse/tratamento farmacológico , Sepse/patologia , Animais , Biomarcadores , Caspase 3 , Fragmentação do DNA/efeitos dos fármacos , Feminino , Genes bcl-2 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos , Ratos Sprague-Dawley , Sepse/enzimologia , Sepse/genética , Espectrina/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Linfócitos T/patologia
7.
Bioorg Med Chem Lett ; 18(11): 3200-5, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18477508

RESUMO

A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer.


Assuntos
Hidrocarbonetos Halogenados/síntese química , Hidrocarbonetos Halogenados/farmacologia , Naftalenos/síntese química , Naftalenos/farmacologia , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Técnicas de Química Combinatória , Diabetes Mellitus/induzido quimicamente , Modelos Animais de Doenças , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Haplorrinos , Hidrocarbonetos Halogenados/química , Camundongos , Estrutura Molecular , Naftalenos/química , Neoplasias/induzido quimicamente , Organofosfonatos/química , Ratos
8.
Bioorg Med Chem Lett ; 18(6): 2048-54, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18291643

RESUMO

A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.


Assuntos
Artrite Experimental/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Cães , Cobaias , Humanos , Macaca mulatta , Estrutura Molecular , Quinolinas/farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética
9.
Br J Pharmacol ; 141(4): 689-97, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14744804

RESUMO

1. Caspases, key enzymes in the apoptosis pathway, have been detected in the brain of HD patients and in animal models of the disease. In the present study, we investigated the neuroprotective properties of a new, reversible, caspase-3-specific inhibitor, M826 (3-([(2S)-2-[5-tert-butyl-3-[[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]amino]-2-oxopyrazin-1(2H)-yl]butanoyl]amino)-5-[hexyl(methyl)amino]-4-oxopentanoic acid), in a rat malonate model of HD. 2. Pharmacokinetic and autoradiography studies after intrastriatal (i.str.) injection of 1.5 nmol of M826 or its tritiated analogue [(3)H]M826 indicated that the compound diffused within the entire striatum. The elimination half-life (T(1/2)) of M826 in the rat striatum was 3 h. 3. I.str. injection of 1.5 nmol of M826 10 min after malonate infusion induced a significant reduction (66%) in the number of neurones expressing active caspase-3 in the ipsilateral striatum. 4. Inhibition of active caspase-3 translated into a significant but moderate reduction (39%) of the lesion volume, and of cell death (24%), 24 h after injury. The efficacy of M826 at inhibiting cell death was comparable to that of the noncompetitive NMDA receptor antagonist MK801. 5. These data provide in vivo proof-of-concept of the neuroprotective effects of reversible caspase-3 inhibitors in a model of malonate-induced striatal injury in the adult rat.


Assuntos
Inibidores de Caspase , Inibidores Enzimáticos/farmacologia , Doença de Huntington/induzido quimicamente , Doença de Huntington/tratamento farmacológico , Malonatos , Fármacos Neuroprotetores , Oxidiazóis/farmacologia , Pirazinas/farmacologia , Animais , Autorradiografia , Caspase 3 , Contagem de Células , Morte Celular/efeitos dos fármacos , Difusão , Maleato de Dizocilpina/farmacologia , Inibidores Enzimáticos/farmacocinética , Ensaio de Imunoadsorção Enzimática , Antagonistas de Aminoácidos Excitatórios/farmacologia , Meia-Vida , Doença de Huntington/patologia , Masculino , Neostriado/patologia , Neurônios/efeitos dos fármacos , Oxidiazóis/farmacocinética , Pirazinas/farmacocinética , Ratos , Ratos Sprague-Dawley
10.
Org Lett ; 4(26): 4705-8, 2002 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-12489966

RESUMO

[reaction: see text] The diastereoselective cyclization of bissulfonyl esters was investigated by varying both the size and the placement of the substituent on the tether adjoining the reacting centers. Substitution at either the alpha or beta position relative to the ester moiety gave diastereomeric ratios of (1-3):1, while gamma substitution dramatically increased the diastereomeric ratios to (6-20):1.

11.
Org Lett ; 4(11): 1879-82, 2002 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-12027637

RESUMO

[structure: see text] The total synthesis of the polyether antibiotic ionomycin, a calcium ionophore, is described. The synthesis demonstrates the utility of ring-opening methodologies as applied to the synthesis of polypropionate and deoxypolypropionate subunits, which are found in two of the four fragments in the synthesis.


Assuntos
Antibacterianos/síntese química , Ionomicina/síntese química , Aldeídos/química , Cálcio/química , Hidroxilação , Indicadores e Reagentes , Ozônio/química , Estereoisomerismo
12.
Bioorg Med Chem Lett ; 17(6): 1671-4, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17251019

RESUMO

Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact on the treatment of several degenerative diseases. Here we report the synthesis of reversible inhibitors via a solid-support palladium-catalyzed amination of 3-bromopyrazinones and the discovery of a pan-caspase reversible inhibitor.


Assuntos
Inibidores de Caspase , Paládio/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Aminação , Catálise , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes , Espectrometria de Massas , Proteínas Recombinantes/química , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 15(4): 1173-80, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15686936

RESUMO

The iterative process for the discovery of a series of pyrazinone mono-amides as potent, selective and reversible non-peptide caspase-3 inhibitors (e.g., M826 and M867) is reported. These compounds display potent anti apoptotic activities in a number of cell based systems in vitro as well as in several animal models in vivo.


Assuntos
Amidas/síntese química , Inibidores de Caspase , Amidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3 , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Leucócitos/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Pirazinas/síntese química , Pirazinas/farmacologia , Ratos , Relação Estrutura-Atividade
14.
J Biol Chem ; 279(27): 27905-14, 2004 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-15067000

RESUMO

Apoptotic markers consist of either caspase substrate cleavage products or phenotypic changes that manifest themselves as a consequence of caspase-mediated substrate cleavage. We have shown recently that pharmacological inhibitors of caspase activity prevent the appearance of two such apoptotic manifestations, alphaII-spectrin cleavage and DNA fragmentation, but that blockade of the latter required a significantly higher concentration of inhibitor. We investigated this phenomenon through the use of a novel radiolabeled caspase inhibitor, [(125)I]M808, which acts as a caspase active site probe. [(125)I]M808 bound to active caspases irreversibly and with high sensitivity in apoptotic cell extracts, in tissue extracts from several commonly used animal models of cellular injury, and in living cells. Moreover, [(125)I]M808 detected active caspases in septic mice when injected intravenously. Using this caspase probe, an active site occupancy assay was developed and used to measure the fractional inhibition required to block apoptosis-induced DNA fragmentation. In thymocytes, occupancy of up to 40% of caspase active sites had no effect on DNA fragmentation, whereas inhibition of half of the DNA cleaving activity required between 65 and 75% of active site occupancy. These results suggest that a high and persistent fractional inhibition will be required for successful caspase inhibition-based therapies.


Assuntos
Caspases/química , Fragmentação do DNA , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Apoptose , Sítios de Ligação , Western Blotting , Inibidores de Caspase , Ceco/patologia , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Radioisótopos do Iodo/metabolismo , Células Jurkat , Cinética , Camundongos , Modelos Químicos , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Sensibilidade e Especificidade , Sepse , Timo/citologia , Distribuição Tecidual
15.
J Biol Chem ; 277(33): 30128-36, 2002 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-12058036

RESUMO

Hypoxia-ischemia (H-I) in the developing brain results in brain injury with prominent features of both apoptosis and necrosis. A peptide-based pan-caspase inhibitor is neuroprotective against neonatal H-I brain injury, suggesting a central role of caspases in brain injury. Because previously studied peptide-based caspase inhibitors are not potent and are only partially selective, the exact contribution of specific caspases and other proteases to injury after H-I is not clear. In this study, we explored the neuroprotective effects of a small, reversible caspase-3 inhibitor M826. M826 selectively and potently inhibited both caspase-3 enzymatic activity and apoptosis in cultured cells in vitro. In a rat model of neonatal H-I, M826 blocked caspase-3 activation and cleavage of its substrates, which begins 6 h and peaks 24 h after H-I. Although M826 significantly reduced DNA fragmentation and brain tissue loss, it did not prevent calpain activation in the cortex. This activation, which is associated with excitotoxic/necrotic cell injury, occurred within 30 min to 2 h after H-I even in the presence of M826. Similar to calpain activation, we found evidence of caspase-2 processing within 30 min to 2 h after H-I that was not affected by M826. Caspase-2 processing appeared to be secondary to calpain-mediated cleavage and was not associated with caspase-2 activation. These data suggest that caspase-3 specifically contributes to delayed cell death and brain injury after neonatal H-I and that calpain activation is associated with and likely a marker for the early component of excitotoxic/necrotic brain injury previously demonstrated in this model.


Assuntos
Animais Recém-Nascidos , Apoptose , Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Hipóxia-Isquemia Encefálica/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Oxidiazóis/farmacologia , Pirazinas/farmacologia , Animais , Caspase 3 , Hidrólise , Hipóxia-Isquemia Encefálica/patologia , Ratos , Ratos Sprague-Dawley
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA