Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
J Med Chem ; 59(6): 2328-42, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-26812066

RESUMO

Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridonas/síntese química , Piridonas/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Animais , Antineoplásicos/farmacocinética , Cristalografia por Raios X , Desenho de Fármacos , Descoberta de Drogas , Humanos , Camundongos , Modelos Moleculares , Piridonas/farmacocinética , Relação Estrutura-Atividade , Triazóis/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Med Chem ; 58(5): 2417-30, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25699405

RESUMO

The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.


Assuntos
Descoberta de Drogas , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinolinas/farmacologia , Triazóis/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Triazóis/química , Triazóis/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Med Chem ; 55(17): 7667-85, 2012 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-22876881

RESUMO

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.


Assuntos
Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Modelos Moleculares
5.
Bioorg Med Chem Lett ; 19(22): 6307-12, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19819693

RESUMO

Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.


Assuntos
Inibidores da Angiogênese/farmacologia , Apoptose/fisiologia , Neovascularização Fisiológica/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Animais , Sobrevivência Celular , Humanos , Camundongos , Camundongos Nus , Fosforilação , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Med Chem ; 51(10): 2879-82, 2008 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-18426196

RESUMO

Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.


Assuntos
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridazinas/síntese química , Triazóis/síntese química , Animais , Cristalografia por Raios X , Fator de Crescimento de Hepatócito/fisiologia , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Fosforilação , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridazinas/química , Piridazinas/farmacocinética , Piridazinas/farmacologia , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacocinética , Triazóis/farmacologia
7.
Bioorg Med Chem Lett ; 16(17): 4554-8, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16784854

RESUMO

As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.


Assuntos
Amidas/química , Amidas/farmacologia , Apoptose/efeitos dos fármacos , Oxazóis/química , Oxazóis/farmacologia , Amidas/síntese química , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Estrutura Molecular , Oxazóis/síntese química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Bioorg Med Chem Lett ; 16(5): 1191-6, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16377187

RESUMO

Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.


Assuntos
Antimitóticos/síntese química , Antimitóticos/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Animais , Antimitóticos/química , Antimitóticos/classificação , Biopolímeros/química , Biopolímeros/metabolismo , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/classificação , Conformação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA