Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 61(9): 3823-3841, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29683659

RESUMO

ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Desenho de Fármacos , Piridinas/farmacocinética , Quinolinas/farmacocinética , Quinolonas/farmacologia , Quinolonas/farmacocinética , Administração Oral , Proteínas Mutadas de Ataxia Telangiectasia/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Disponibilidade Biológica , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases , Piridinas/administração & dosagem , Piridinas/química , Quinolinas/administração & dosagem , Quinolinas/química , Quinolonas/administração & dosagem , Quinolonas/química , Relação Estrutura-Atividade , Especificidade por Substrato
2.
Bioorg Med Chem ; 26(4): 945-956, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28818461

RESUMO

Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.


Assuntos
Proteína ADAM17/antagonistas & inibidores , Inibidores Enzimáticos/química , Proteína ADAM17/metabolismo , Administração Tópica , Animais , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Ácidos Hidroxâmicos/química , Camundongos , Camundongos Pelados , Microssomos Hepáticos/metabolismo , Oxazolona/toxicidade , Psoríase/tratamento farmacológico , Psoríase/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/prevenção & controle , Dermatopatias/veterinária , Solubilidade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
3.
Bioorg Med Chem Lett ; 27(13): 3030-3035, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28526367

RESUMO

We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kß and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50mg/kg twice daily orally) in the MCF7 xenograft model in mice.


Assuntos
Descoberta de Drogas , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Classe I de Fosfatidilinositol 3-Quinases , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 27(8): 1848-1853, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28274635

RESUMO

Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.


Assuntos
Proteína ADAM17/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/química , Proteína ADAM17/metabolismo , Administração Tópica , Humanos , Psoríase/tratamento farmacológico , Psoríase/enzimologia
5.
J Med Chem ; 59(17): 7801-17, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27528113

RESUMO

Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.


Assuntos
Antineoplásicos/química , Compostos Heterocíclicos com 2 Anéis/química , Proteínas Nucleares/antagonistas & inibidores , Piperazinas/química , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Células CACO-2 , Proteínas de Ciclo Celular , Cristalografia por Raios X , Cães , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Xenoenxertos , Humanos , Camundongos SCID , Transplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacologia , Conformação Proteica , Pirazóis , Piridazinas , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
6.
J Med Chem ; 59(13): 6281-92, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27259031

RESUMO

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.


Assuntos
Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Quinolinas/administração & dosagem , Quinolinas/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Bioorg Med Chem Lett ; 25(22): 5155-62, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26475521

RESUMO

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 Xenoenxerto
8.
Bioorg Med Chem Lett ; 25(13): 2679-85, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25980912

RESUMO

Starting from compound 1, a potent PI3Kα inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3Kα and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Kα, with excellent kinase selectivity.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Sequência de Aminoácidos , Sítios de Ligação , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Modelos Moleculares , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/química , Proteínas Mutantes/genética , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/genética , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA