RESUMO
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.
Assuntos
Adenosina/farmacologia , Doenças Autoimunes/prevenção & controle , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inflamação/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Adenosina/química , Adenosina/metabolismo , Animais , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Modelos Animais de Doenças , Descoberta de Drogas , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Quinolinas/química , Quinolinas/metabolismo , Ratos Endogâmicos Lew , Células Sf9 , Relação Estrutura-AtividadeRESUMO
Through the analysis of X-ray crystallographic information and previous SAR studies, a novel series of protein kinase B (PKB/AKT) inhibitors was developed. The compounds showed nanomolar inhibition of AKT1 and were selective against cyclin-dependent kinase 2 (CDK2).
Assuntos
Amidas/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Técnicas de Química Sintética , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Intracellular levels of the hypoxia-inducible transcription factor (HIF) are regulated under normoxic conditions by prolyl hydroxylases (PHD1, 2, and 3). Treatment of cells with PHD inhibitors stabilizes HIF-1α, eliciting an artificial hypoxic response that includes the transcription of genes involved in erythropoiesis, angiogenesis, and glycolysis. The different in vivo roles of the three PHD isoforms are not yet known, making a PHD-selective inhibitor useful as a biological tool. Although several chemical series of PHD inhibitors have been described, significant isoform selectivity has not been reported. Here we report the synthesis and activity of dipeptidyl analogues derived from a potent but non-selective quinolone scaffold. The compounds were prepared by Pd-catalyzed reductive carbonylation of the 6-iodoquinolone derivative to form the aldehyde directly, which was then attached to a solid support via reductive amination. Amino acids were coupled, and the resulting dipeptidyl-quinolone derivatives were screened, revealing retention of PHD inhibitory activity but an altered PHD1, 2, and 3 selectivity profile. The compounds were found to be â¼10-fold more potent against PHD1 and PHD3 than against PHD2, whereas the specific parent compound had shown no appreciable selectivity among the different PHD isoforms.
Assuntos
Dipeptídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Isoenzimas/antagonistas & inibidores , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , Quinolonas/farmacologia , Técnicas de Química Combinatória , Dipeptídeos/síntese química , Dipeptídeos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isoenzimas/química , Isoenzimas/metabolismo , Estrutura Molecular , Pró-Colágeno-Prolina Dioxigenase/química , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Quinolonas/síntese química , Quinolonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.
Assuntos
Ftalazinas/química , Ftalazinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Desenho de Fármacos , Proteínas Hedgehog , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Camundongos , Ftalazinas/síntese química , Transdução de Sinais , Receptor SmoothenedRESUMO
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
Assuntos
Antineoplásicos/química , Isoquinolinas/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Tiadiazóis/química , Tiazóis/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Domínio Catalítico , Cristalografia por Raios X , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Camundongos , Neoplasias/tratamento farmacológico , Fosforilação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/farmacocinética , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
Through a combination of screening and structure-based rational design, we have discovered a series of N(1)-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.
Assuntos
Antineoplásicos/química , Azóis/química , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Azóis/farmacocinética , Azóis/uso terapêutico , Sítios de Ligação , Cristalografia por Raios X , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Desenho de Fármacos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumor protein 53 (p53) is a critical regulator of cell cycle and apoptosis that is frequently disabled in human tumors. In many tumor types, p53 is deleted or mutated, but in others p53 is inactivated by overexpression or amplification of its negative regulator mouse double minute 2 (MDM2). A high-throughput screening effort identified 6,7-bis(4-bromophenyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine as a potent inhibitor of the MDM2-p53 protein-protein interaction. This screening hit was found to be chemically unstable and difficult to handle due to poor DMSO solubility. Co-crystallization with the target protein helped to direct further optimization and provided a tractable lead series of novel MDM2-p53 inhibitors. In cellular assays, these compounds were shown to upregulate p53 protein levels and p53 signaling and to cause p53-dependent inhibition of proliferation and apoptosis.
Assuntos
Descoberta de Drogas , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirimidinas/química , Pirimidinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Ligação Proteica/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Linhagem Celular Tumoral , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Deregulation of the receptor tyrosine kinase c-Kit is associated with an increasing number of human diseases, including certain cancers and mast cell diseases. Interference of c-Kit signaling with multi-kinase inhibitors has been shown clinically to successfully treat gastrointestinal stromal tumors and mastocytosis. Targeted therapy of c-Kit activity may provide therapeutic advantages against off-target effects for non-oncology applications. A new structural class of c-Kit inhibitors is described, including in vitro c-Kit potency, kinase selectivity, and the observed binding mode.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Isoxazóis/síntese química , Isoxazóis/farmacologia , Proteínas Proto-Oncogênicas c-kit/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/metabolismo , Amidas/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Humanos , Isoxazóis/química , Conformação Molecular , Estrutura Molecular , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacosRESUMO
A potent and selective c-Kit inhibitor 20 was identified through a structure-activity relationship study. In an in vivo mouse model of mast cell activation, 20 blocked the SCF-induced histamine release with an EC(50) of 26 nM.
Assuntos
Química Farmacêutica/métodos , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/química , Animais , Desenho de Fármacos , Liberação de Histamina/efeitos dos fármacos , Concentração Inibidora 50 , Cinética , Sistema de Sinalização das MAP Quinases , Mastócitos/metabolismo , Camundongos , Ratos , Fator de Células-Tronco/metabolismo , Relação Estrutura-AtividadeRESUMO
Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridonas/síntese química , Quinazolinas/síntese química , Administração Oral , Animais , Cristalografia por Raios X , Liberação de Histamina/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The LPA(2) protein is overexpressed in many tumor cells. We report the optimization of a series of LPA(2) antagonists using calcium mobilization assay (aequorin assay) that led to the discovery of the first reported inhibitors selective for LPA(2). Key compounds were evaluated in vitro for inhibition of LPA(2) mediated Erk activation and proliferation of HCT-116 cells. These compounds could be used to evaluate the benefits of LPA(2) inhibition both in vitro and in vivo.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Técnicas de Química Combinatória , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Antineoplásicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Estrutura Molecular , Células Tumorais CultivadasRESUMO
We report the development of the novel N-substituted benzimidazole 11 as a potent and selective human formyl peptide receptor-like 1 (hFPRL1) agonist. This compound and its less active enantiomer 12 were identified as useful tools for studying receptor function in vitro.
Assuntos
Mediadores da Inflamação/fisiologia , Sondas Moleculares/análise , Sondas Moleculares/síntese química , Receptores de Formil Peptídeo/fisiologia , Receptores de Lipoxinas/fisiologia , Animais , Benzimidazóis/agonistas , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Células CHO , Inibição de Migração Celular , Quimiotaxia de Leucócito/fisiologia , Cricetinae , Cricetulus , Humanos , Mediadores da Inflamação/agonistas , Interleucina-6/metabolismo , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptores de Formil Peptídeo/agonistas , Receptores de Formil Peptídeo/sangue , Receptores de Lipoxinas/agonistas , Receptores de Lipoxinas/sangueRESUMO
We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.
Assuntos
Inibidores da Angiogênese/síntese química , Indóis/síntese química , Indóis/farmacocinética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Disponibilidade Biológica , Linhagem Celular , Meia-Vida , Indóis/farmacologia , Concentração Inibidora 50 , Ratos , Relação Estrutura-AtividadeRESUMO
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described.
Assuntos
Inibidores da Angiogênese/síntese química , Pirimidinas/farmacocinética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Taxa de Depuração Metabólica , Farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC(50)=19 nM), respectively. The synthesis and SAR of these compounds are described.