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1.
J Org Chem ; 82(19): 10376-10387, 2017 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-28877441

RESUMO

An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies.


Assuntos
Antivirais/síntese química , Glicina/análogos & derivados , Imidazóis/síntese química , Piranos/farmacologia , Pirrolidinas/síntese química , Compostos de Espiro/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Estrutura Molecular , Piranos/síntese química , Piranos/química , Pirrolidinas/química , Pirrolidinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Proteínas não Estruturais Virais/metabolismo
2.
Virology ; 444(1-2): 343-54, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23896639

RESUMO

The hepatitis C virus NS5A protein is an established and clinically validated target for antiviral intervention by small molecules. Characterizations are presented of compounds identified as potent inhibitors of HCV replication to provide insight into structural elements that interact with the NS5A protein. UV-activated cross linking and affinity isolation was performed with one series to probe the physical interaction between the inhibitors and the NS5A protein expressed in HCV replicon cells. Resistance mapping with the second series was used to determine the functional impact of specific inhibitor subdomains on the interaction with NS5A. The data provide evidence for a direct high-affinity interaction between these inhibitors and the NS5A protein, with the interaction dependent on inhibitor stereochemistry. The functional data supports a model of inhibition that implicates inhibitor binding by covalently combining distinct pharmacophores across an NS5A dimer interface to achieve maximal inhibition of HCV replication.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , RNA Replicase/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Farmacorresistência Viral , Humanos , Ligação Proteica
3.
Mol Pharmacol ; 69(4): 1396-404, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16399850

RESUMO

Neurotrophins are a family of secreted proteins that play an important role in the development, differentiation, and survival of neurons. Studies also suggest that aberrant neurotrophin signaling may play a role in processes underlying disease states such as schizophrenia, Alzheimer's disease, and depression. Whereas the development of agents that selectively stimulate neurotrophin signaling has proven to be difficult, compounds have been identified that potentiate neurotrophin 3 (NT-3)-mediated activation of trk A. In the present studies, we extend those initial observations to identify compounds that also potentiate NT-3-mediated activation of trk B. Compound potentiation of NT-3 was observed using several readouts of transfected and endogenous trk receptor activity, including trk receptor phosphorylation, mitogen-activated protein kinase phosphorylation, reporter assay activity (beta-lactamase and luciferase), cell survival and neurite extension assays. Studies using chimeric trk receptors demonstrated that the extracellular domain is essential for compound potentiation and rule out interaction with intracellular signaling molecules as a mechanism of compound activity. Thus, the present studies demonstrate that trk B receptor activity can be potentiated by small-molecule compounds via the extracellular domain of the receptor and provide reagents for further evaluating the role of NT-3-mediated trk A and trk B activity in vivo.


Assuntos
Neurotrofina 3/farmacologia , Receptor trkB/agonistas , Animais , Western Blotting , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cricetinae , DNA Complementar , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Ratos , Receptor trkB/genética , Receptor trkB/metabolismo , Transdução de Sinais
4.
Bioorg Med Chem Lett ; 13(8): 1419-23, 2003 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-12668003

RESUMO

The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.


Assuntos
Antifúngicos/química , Antifúngicos/farmacocinética , Compostos Aza/síntese química , Compostos Aza/farmacocinética , Administração Oral , Animais , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Compostos Aza/química , Compostos Aza/farmacologia , Glicosídeos/química , Indenos , Injeções Intravenosas , Camundongos , Testes de Sensibilidade Microbiana , Compostos de Espiro/química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
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