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
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/metabolismoRESUMO
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-AtividadeRESUMO
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/enzimologiaRESUMO
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
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/farmacologiaRESUMO
The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pKa modulation are discussed.
Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Fenômenos Químicos , Físico-Química , Receptores ErbB/metabolismo , Flúor/química , Gefitinibe , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Ratos , Relação Estrutura-Atividade , Tiazóis/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The structure-activity relationship of a novel subseries of 4-anilinoquinazoline EGFR inhibitors substituted at the C-6 position with carbon-linked side chains has been investigated. This exploration has led to the discovery of novel aminomethyl carboxamides with good biological, pharmacokinetic and physical properties.
Assuntos
Receptores ErbB/antagonistas & inibidores , Quinazolinas/química , Quinazolinas/farmacologia , Administração Oral , Animais , Cães , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
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.