Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Clin Cancer Res ; 13(9): 2728-37, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17473206

RESUMO

PURPOSE: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. EXPERIMENTAL DESIGN: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. RESULTS: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. CONCLUSIONS: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.


Assuntos
Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases , Administração Oral , Animais , Antineoplásicos Alquilantes/uso terapêutico , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Modelos Animais de Doenças , Cães , Sinergismo Farmacológico , Feminino , Haplorrinos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Endogâmicos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Mol Cancer Ther ; 5(4): 995-1006, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16648571

RESUMO

ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 micromol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-beta, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED50 = 1.5-5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC50 corrected for plasma protein binding = 0.08 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer.


Assuntos
Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Compostos de Fenilureia/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Células 3T3 , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Córnea , Edema , Feminino , Camundongos , Neovascularização Fisiológica/efeitos dos fármacos , Fosforilação , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/fisiologia , Útero/efeitos dos fármacos , Útero/fisiopatologia
4.
Bioorg Med Chem Lett ; 12(23): 3383-6, 2002 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-12419366

RESUMO

The synthesis and biological evaluation of a series of functionalized pyrrolidine- and piperidine-containing analogues of our lead LTA(4) hydrolase inhibitor, SC-57461A, is described. A number of compounds showed excellent potency in our in vitro screens and several demonstrated good oral activity in a mouse ex vivo assay. These efforts led to the identification of SC-56938 (14) as a potent, orally active inhibitor of LTA(4) hydrolase.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Piperidinas/química , Piperidinas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , beta-Alanina/análogos & derivados , beta-Alanina/química , Administração Oral , Animais , Humanos , Concentração Inibidora 50 , Camundongos , Relação Estrutura-Atividade
5.
J Med Chem ; 45(16): 3482-90, 2002 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12139459

RESUMO

Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention in these disease states, since the action of this enzyme is the rate-limiting step in the production of LTB(4). Our previous efforts focused on the exploration of a series of analogues related to screening hit SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) and resulted in the identification of potent, orally active inhibitors such as 2. Additional structure-activity relationship studies around this structural class resulted in the identification of a series of alpha-, beta-, and gamma-amino acid analogues that are potent inhibitors of the LTA(4) hydrolase enzyme and demonstrated good oral activity in a mouse ex vivo whole blood LTB(4) production assay. The efforts leading to the identification of clinical candidate SC-57461A (8d, 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described.


Assuntos
Inibidores Enzimáticos/síntese química , Epóxido Hidrolases/antagonistas & inibidores , beta-Alanina/síntese química , Administração Oral , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Leucotrieno A4/biossíntese , Leucotrieno A4/sangue , Camundongos , Relação Estrutura-Atividade , beta-Alanina/análogos & derivados , beta-Alanina/química , beta-Alanina/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...