RESUMO
A new series of Quinazoline Ether Inhibitor which potently inhibits VEGFR-2 and PDGFR tyrosine kinases is described here. In vitro, pharmacokinetics and in vivo evaluations led to the selection of AZD2932.
Assuntos
Éteres/síntese química , Éteres/farmacologia , Quinazolinas/síntese química , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Algoritmos , Animais , Química Farmacêutica/métodos , Cães , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Modelos Químicos , Fosforilação , Quinazolinas/farmacologia , RatosRESUMO
A new series of quinoline ether inhibitors, which potently and selectively inhibit PDGFR tyrosine kinases, is described in this Letter. Compounds 23 and 33 are selective, low nanomolar inhibitors of PDGFRα and ß, display good pharmacokinetics in rat and dog and are active in vivo at low doses when given orally twice daily. Further evaluation of these compounds is warranted.
Assuntos
Éteres/farmacologia , Quinolinas/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Animais , Cães , Relação Dose-Resposta a Droga , Descoberta de Drogas , Proteínas Tirosina Quinases/antagonistas & inibidores , RatosRESUMO
Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzodioxóis/síntese química , Benzodioxóis/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Quinazolinas/síntese química , Quinazolinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/química , Células 3T3 , Animais , Antineoplásicos/farmacocinética , Benzodioxóis/farmacocinética , Proliferação de Células/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Indicadores e Reagentes , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Invasividade Neoplásica/prevenção & controle , Quinazolinas/farmacocinética , Ratos , Solubilidade , Relação Estrutura-Atividade , Termodinâmica , Transplante Heterólogo , Quinases da Família src/biossínteseRESUMO
A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.
Assuntos
Receptor alfa de Estrogênio/metabolismo , Umbeliferonas/química , Umbeliferonas/farmacologia , Administração Oral , Animais , Linhagem Celular Tumoral , Cumarínicos/química , Cumarínicos/farmacocinética , Cumarínicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Receptor alfa de Estrogênio/análise , Humanos , Simulação de Acoplamento Molecular , Ratos , Umbeliferonas/farmacocinéticaRESUMO
Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Dioxóis/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/síntese química , Células 3T3 , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Proteína Tirosina Quinase CSK , Dioxóis/farmacocinética , Dioxóis/farmacologia , Camundongos , Modelos Moleculares , Invasividade Neoplásica , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Ratos Nus , Relação Estrutura-Atividade , Tirosina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família srcRESUMO
We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC(50) 0.02 microM, range 0.001-0.04 microM), which are comparatively less potent vs Flt-1 tyrosine kinase (median IC(50) 0.55 microM, range 0.02-1.6 microM). The compounds also retain some inhibitory activity against the tyrosine kinase associated to the endothelial growth factor receptor (EGFR) (median IC(50) 0.2 microM, range 0.075-0.8 microM) but demonstrate selectivity vs that associated to the FGF receptor 1 (median IC(50) 2.5 microM, range 0.9-19 microM). This selectivity profile is also evident in a growth factor-stimulated human endothelial cell (HUVEC) proliferation assay (i.e., inhibition of VEGF > EGF > FGF), with inhibition of VEGF-induced proliferation being achieved at nanomolar concentrations (median IC(50) 0.06 microM). Further examination of compound 2 (ZD6474) in recombinant enzyme assays revealed excellent selectivity for the inhibition of KDR tyrosine kinase (IC(50) 0.04 microM) vs the kinase activity of erbB2, MEK, CDK-2, Tie-2, IGFR-1R, PDK, PDGFRbeta, and AKT (IC(50) range: 1.1 to >100 microM). Anilinoquinazolines possessing basic C-7 side chains exhibited markedly improved aqueous solubility over previously described anilinoquinazolines possessing neutral C-7 side chains (up to 500-fold improvement at pH 7.4). In addition, aqueous solubility of the neutral fraction present at pH 7.4 of the basic subseries of anilinoquinazoline proved to be higher than that of the neutral analogue 1 (ZD4190). Oral administration of representative compounds to mice (50 mg/kg) produced plasma levels between 0.2 and 3 microM at 24 h after dosing. Our development candidate 2 demonstrated a very attractive in vitro profile combined with excellent solubility (330 microM at pH 7.4) and good oral bioavailability in rat and dog (> 80 and > 50%, respectively). This compound demonstrated highly significant, dose-dependent, antitumor activity in athymic mice. Once daily oral administration of 100 mg/kg of compound 2 for 21 days inhibited the growth of established Calu-6 lung carcinoma xenografts by 79% (P < 0.001, Mann Whitney rank sum test), and substantial inhibition (36%, P < 0.02) was evident with 12.5 mg/kg/day.
Assuntos
Inibidores da Angiogênese/síntese química , Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinazolinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Administração Oral , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Disponibilidade Biológica , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Cães , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Piperidinas/administração & dosagem , Piperidinas/síntese química , Piperidinas/farmacologia , Quinazolinas/administração & dosagem , Quinazolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Receptor 1 de Fatores de Crescimento do Endotélio VascularRESUMO
AZD0530, an orally available Src inhibitor, demonstrated potent antimigratory and anti-invasive effects in vitro, and inhibited metastasis in a murine model of bladder cancer. Antiproliferative activity of AZD0530 in vitro varied between cell lines (IC(50) 0.2 ->10µM). AZD0530 inhibited tumor growth in 4/10 xenograft models tested and dynamically inhibited in vivo phosphorylation of Src substrates paxillin and FAK in both growth-inhibition-resistant and -sensitive xenografts. The activity of AZD0530 in NBT-II bladder cancer cells in vitro was consistent with inhibition of cell migration and stabilization of cell-cell adhesion. These data suggest a dominant anti-invasive pharmacology for AZD0530 that may limit tumor progression in a range of cancers. AZD0530 is currently in Phase II clinical trials.