RESUMO
A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
Assuntos
Antineoplásicos/farmacologia , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Quinina/análogos & derivados , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologia , Modelos Moleculares , Estrutura Molecular , Quinina/síntese química , Quinina/química , Quinina/farmacologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Solubilidade , Relação Estrutura-AtividadeRESUMO
Attempts to lock the active conformation of compound 4, a PI3Kß/δ inhibitor (PI3Kß cell IC50 0.015µM), led to the discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3Kß/δ inhibitors. Compound 10 proved exquisitely potent and selective: PI3Kß cell IC50 0.0011µM in PTEN null MDA-MB-468 cell and PI3Kδ cell IC50 0.014µM in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3Kß/δ preclinical candidates.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Benzopiranos/química , Benzopiranos/uso terapêutico , PTEN Fosfo-Hidrolase/genética , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzopiranos/farmacocinética , Benzopiranos/farmacologia , Linhagem Celular Tumoral , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Cães , Deleção de Genes , Humanos , Masculino , Camundongos Nus , Simulação de Acoplamento Molecular , Morfolinos/química , Morfolinos/farmacocinética , Morfolinos/farmacologia , Morfolinos/uso terapêutico , Próstata/efeitos dos fármacos , Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
We report the discovery and optimisation of a series of 8-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-2-morpholino-4-oxo-chromene-6-carboxamides, leading to compound 16 as a potent and selective PI3Kß/δ inhibitor: PI3Kß cell IC50 0.012 µM (in PTEN null MDA-MB-468 cell) and PI3Kδ cell IC50 0.047 µM (in Jeko-1 B-cell), with good pharmacokinetics and physical properties. In vivo, 16 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-deficient PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Compound 16 was selected as a preclinical candidate for the treatment of PTEN-deficient tumours.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isoenzimas/antagonistas & inibidores , Morfolinos/química , Morfolinos/farmacologia , PTEN Fosfo-Hidrolase/genética , Inibidores de Fosfoinositídeo-3 Quinase , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , FosforilaçãoRESUMO
Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kß and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.
Assuntos
Antineoplásicos/farmacologia , Oxidiazóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cães , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Piperidinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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
Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kß activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kß/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.
Assuntos
Compostos de Anilina/síntese química , Cromonas/síntese química , Neoplasias Experimentais/tratamento farmacológico , PTEN Fosfo-Hidrolase/deficiência , Inibidores de Fosfoinositídeo-3 Quinase , Compostos de Anilina/farmacologia , Animais , Cromonas/farmacologia , Cães , Descoberta de Drogas , Humanos , Masculino , Camundongos , Neoplasias Experimentais/química , Relação Estrutura-AtividadeRESUMO
Starting from TGX-221, we designed a series of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as potent and selective PI3Kß/δ inhibitors. Structure-activity relationships and structure-property relationships around the aniline and the amide substituents are discussed. We identified compounds 17 and 18, which showed profound pharmacodynamic modulation of phosphorylated Akt in the PC3 prostate tumour xenograft, after a single oral dose. Compound 17 also gave significant inhibition of tumour growth in the PC3 prostate tumour xenograft model after chronic oral dosing.
Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Experimentais/tratamento farmacológico , PTEN Fosfo-Hidrolase/deficiência , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Amidas/administração & dosagem , Amidas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/patologia , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
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
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 piperazine series of cyclin-dependent kinase (CDK) inhibitors have been identified. The compounds exhibit excellent physiochemical properties and a novel binding mode, whereby a bridging interaction via a water molecule with Asp 86 of CDK2, leads to selectivity for the CDK family of enzymes over other kinases. Piperazines 2e and 2i were subsequently shown to inhibit tumour growth when dosed orally in a nude mouse xenograft study. Additional chemical series that exploit this unexpected interaction with Asp 86 are also described.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Imidazóis/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Animais , Antineoplásicos/química , Ácido Aspártico/química , Ácido Aspártico/genética , Sítios de Ligação , Técnicas de Química Combinatória , Quinase 2 Dependente de Ciclina/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Camundongos , Camundongos Nus , Estrutura Molecular , Piperazinas/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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 series of novel C-5 substituted anilinoquinazolines, selected on the basis of docking experiments and overlays with ATP in the active site of EGFR tyrosine kinase, have been prepared and found to be potent inhibitors. In vivo pharmacokinetics and disease model activity are discussed.
Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases , Quinazolinas , Ribose/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Feminino , Humanos , Células KB/efeitos dos fármacos , Camundongos , Camundongos Nus , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Starting from a 6,7-substituted quinazoline lead 4, optimisation of 5-substituted quinazolines containing an extended aniline motif led to potent and selective inhibitors of erbB2 receptor tyrosine kinase, and a representative compound 12a inhibited tumour growth in a mouse xenograft model.