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1.
J Med Chem ; 57(5): 1914-31, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24195700

RESUMO

In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Cães , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , Humanos , Modelos Moleculares , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Sulfonamidas/química , Sulfonamidas/farmacocinética
2.
Bioorg Med Chem Lett ; 19(17): 5158-61, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19646866

RESUMO

This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.


Assuntos
Antineoplásicos/química , Benzimidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Aurora Quinases , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Linhagem Celular Tumoral , Humanos , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 19(5): 1409-12, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19186057

RESUMO

Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.


Assuntos
Compostos de Fenilureia/química , Pró-Fármacos/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tiazóis/química , Água/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Aurora Quinases , Masculino , Camundongos , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Tiazóis/farmacocinética , Tiazóis/farmacologia
4.
Bioorg Med Chem Lett ; 18(17): 4880-4, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18678489

RESUMO

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.


Assuntos
Neoplasias Experimentais/tratamento farmacológico , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinazolinas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/enzimologia , Quinazolinas/química , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 18(14): 3978-81, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18579375

RESUMO

We demonstrate a fragment-based lead discovery method that combines site-directed ligand discovery with dynamic combinatorial chemistry. Our technique targets dynamic combinatorial screening to a specified region of a protein by using reversible disulfide chemistry. We have used this technology to rapidly identify inhibitors of the drug target Aurora A that span the purine-binding site and the adaptive pocket of the kinase. The binding mode of a noncovalent inhibitor has been further characterized through crystallography.


Assuntos
Química Farmacêutica/métodos , Técnicas de Química Combinatória/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Aurora Quinases , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Ligantes , Espectrometria de Massas/métodos , Modelos Químicos , Estrutura Molecular , Purinas/química , Relação Estrutura-Atividade
6.
Science ; 310(5750): 1022-5, 2005 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-16284179

RESUMO

We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-alpha subunits.


Assuntos
Indóis/química , Indóis/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/química , Biotinilação , Fenômenos Químicos , Físico-Química , Cristalografia por Raios X , Dimerização , Fluorescência , Hidrogênio/química , Interações Hidrofóbicas e Hidrofílicas , Indóis/síntese química , Cinética , Espectrometria de Massas , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Conformação Proteica , Subunidades Proteicas/química , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Mol Cell Biol ; 22(13): 4477-90, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12052858

RESUMO

The fission yeast Dbf4 homologue Dfp1 has a well-characterized role in regulating the initiation of DNA replication. Sequence analysis of Dfp1 homologues reveals three highly conserved regions, referred to as motifs N, M, and C. To determine the roles of these conserved regions in Dfp1 function, we have generated dfp1 alleles with mutations in these regions. Mutations in motif N render cells sensitive to a broad range of DNA-damaging agents and replication inhibitors, yet these mutant proteins are efficient activators of Hsk1 kinase in vitro. In contrast, mutations in motif C confer sensitivity to the alkylating agent methyl methanesulfonate (MMS) but, surprisingly, not to UV, ionizing radiation, or hydroxyurea. Motif C mutants are poor activators of Hsk1 in vitro but can fulfill the essential function(s) of Dfp1 in vivo. Strains carrying dfp1 motif C mutants have an intact mitotic and intra-S-phase checkpoint, and epistasis analysis indicates that dfp1 motif C mutants function outside of the known MMS damage repair pathways, suggesting that the observed MMS sensitivity is due to defects in recovery from DNA damage. The motif C mutants are most sensitive to MMS during S phase and are partially suppressed by deletion of the S-phase checkpoint kinase cds1. Following treatment with MMS, dfp1 motif C mutants exhibit nuclear fragmentation, chromosome instability, precocious recombination, and persistent checkpoint activation. We propose that Dfp1 plays at least two genetically separable roles in the DNA damage response in addition to its well-characterized role in the initiation of DNA replication and that motif C plays a critical role in the response to alkylation damage, perhaps by restarting or stabilizing stalled replication forks.


Assuntos
Proteínas de Ciclo Celular , Cromossomos Fúngicos , Proteínas Fúngicas/genética , Proteínas Serina-Treonina Quinases , Fase S/genética , Proteínas de Saccharomyces cerevisiae , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces/genética , Alquilação , Sequência de Aminoácidos , Antineoplásicos Alquilantes/farmacologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/genética , Núcleo Celular/ultraestrutura , Quinase 1 do Ponto de Checagem , Sequência Conservada , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Replicação do DNA/efeitos dos fármacos , Proteínas Fúngicas/metabolismo , Metanossulfonato de Metila/farmacologia , Mitose , Mutação , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Recombinação Genética , Schizosaccharomyces/citologia , Schizosaccharomyces/efeitos dos fármacos
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