Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Blood ; 120(23): 4621-34, 2012 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-23034282

RESUMO

The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eµ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies.


Assuntos
Acrilatos/farmacologia , Carioferinas/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/farmacologia , Acrilatos/química , Acrilatos/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cristalografia por Raios X , Humanos , Immunoblotting , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Carioferinas/química , Carioferinas/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Camundongos , Camundongos SCID , Camundongos Transgênicos , Microscopia Confocal , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Triazóis/química , Triazóis/metabolismo , Proteína Exportina 1
2.
3.
Bioorg Med Chem Lett ; 19(13): 3445-8, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19464885

RESUMO

A series of alpha-sulfone piperidine hydroxamate TACE inhibitors 11a-n bearing a quinolinyl methyl P1' group was prepared, and their activity was compared to analogous alpha- and beta-sulfone piperidine hydroxamates with a butynyloxy P1' group. The quinolinyl methyl P1' group affords increased inhibitory enzyme activity relative to the corresponding butynyloxy P1' analogs in the alpha-sulfone piperidine hydroxamate series, and greater selectivity than the corresponding butynyloxy P1' analogs in the beta-sulfone piperidine hydroxamate series.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Ácidos Hidroxâmicos/síntese química , Piperidinas/química , Inibidores de Proteases/síntese química , Sulfonas/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Camundongos , Piperidinas/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Sulfonas/síntese química
4.
Curr Med Chem ; 9(12): 1145-65, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12052169

RESUMO

Resistance to antibiotics is currently a major health concern in treating infectious diseases. The most common mechanism of resistance to beta-lactam antibiotics is the production of beta-lactamases, which destroy beta-lactam antibiotics before they reach the bacterial target. Combination therapy, which involves treatment with a beta-lactam antibiotic and a beta-lactamase inhibitor, has been successfully used to control resistance during last two decades. Due to the lack of effectiveness of the currently available beta-lactamase inhibitors against class C enzymes and new variants of beta-lactamases, there is a need to develop an inhibitor with broad-spectrum activity. Since the discovery of clavulanic acid, there has been an enormous research effort in this area to identify better antibiotic/inhibitor combinations and to understand the molecular bases for interactions between beta-lactam antibiotics, beta-lactamases, and beta-lactamase inhibitors. This review describes some of the structure- and mechanism-based approaches to design of new beta-lactamase inhibitors and the study of probable mechanisms of inhibition using X-ray, electrospray ionization mass spectrometry, and molecular modeling techniques.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Resistência beta-Lactâmica , Inibidores de beta-Lactamases , Antibacterianos/síntese química , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Cefalosporinas/química , Cefalosporinas/farmacologia , Ácidos Clavulânicos/química , Ácidos Clavulânicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Monobactamas/química , Monobactamas/farmacologia , Ácido Penicilânico/química , Ácido Penicilânico/farmacologia , Relação Estrutura-Atividade , beta-Lactamases/classificação
5.
J Med Chem ; 46(13): 2569-71, 2003 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-12801220
6.
J Med Chem ; 46(12): 2376-96, 2003 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-12773042

RESUMO

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.


Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Piperidinas/síntese química , Inibidores de Proteases/síntese química , Sulfonas/síntese química , Proteínas ADAM , Proteína ADAM17 , Administração Oral , Animais , Sítios de Ligação , Bioensaio , Cartilagem/efeitos dos fármacos , Cartilagem/enzimologia , Bovinos , Cristalografia por Raios X , Diálise , Cães , Haplorrinos , Humanos , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/farmacologia , Masculino , Metaloproteinase 13 da Matriz , Metaloproteinases da Matriz/química , Metaloendopeptidases/antagonistas & inibidores , Camundongos , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Coelhos , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/farmacologia
7.
J Med Chem ; 53(2): 573-85, 2010 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-19950900

RESUMO

Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.


Assuntos
Butiratos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Descoberta de Drogas/métodos , Epóxido Hidrolases/antagonistas & inibidores , Compostos Heterocíclicos/farmacologia , Disponibilidade Biológica , Butiratos/química , Butiratos/uso terapêutico , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/biossíntese , Compostos Heterocíclicos/química , Compostos Heterocíclicos/uso terapêutico , Humanos , Ligantes , Infarto do Miocárdio/tratamento farmacológico , Fragmentos de Peptídeos/química , Solubilidade , Acidente Vascular Cerebral/tratamento farmacológico , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 15(6): 1641-5, 2005 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15745814

RESUMO

Potent and selective TACE and MMP inhibitors utilizing the diazepine and thiazepine ring systems were synthesized and evaluated for biological activity in in vitro and in vivo models of TNF-alpha release. Oral activity in the mouse LPS model of TNF-alpha release was seen. Efficacy in the mouse collagen induced arthritis model was achieved with diazepine 20.


Assuntos
Azepinas/química , Azepinas/farmacologia , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Proteínas ADAM , Proteína ADAM17 , Animais , Azepinas/síntese química , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Químicos , Estrutura Molecular , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA