RESUMO
Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients who have a variety of underlying pathologies such as chronic kidney disease. Treatment with recombinant human EPO (rHuEPO) at supraphysiologic concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients, and it presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF) 1α and HIF2α control the physiologic response to hypoxia and invoke a program of increased erythropoiesis. Levels of HIFα are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs), which tag HIFα for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiologic erythropoietic response and presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863 [2-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido) acetic acid], a pyrimidinetrione-glycinamide low nanomolar inhibitor of PHDs 1-3 that stabilizes HIFα in cell lines, resulting in the production of increased levels of EPO. In normal mice, a single dose of GSK1278863 induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. GSK1278863 significantly increased reticulocytes and red cell mass parameters in preclinical species after once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile, supporting continued clinical development. GSK1278863 is currently in phase 3 clinical trials for treatment of anemia in patients with chronic kidney disease.
Assuntos
Barbitúricos/farmacologia , Drogas em Investigação/farmacologia , Inibidores Enzimáticos/farmacologia , Eritropoese/efeitos dos fármacos , Eritropoetina/agonistas , Glicina/análogos & derivados , Hematínicos/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Animais , Barbitúricos/administração & dosagem , Barbitúricos/efeitos adversos , Barbitúricos/farmacocinética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Cães , Relação Dose-Resposta a Droga , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Eritropoetina/genética , Eritropoetina/metabolismo , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Glicina/farmacologia , Hematínicos/administração & dosagem , Hematínicos/efeitos adversos , Hematínicos/farmacocinética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/agonistas , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Camundongos , Estabilidade Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Testes de Toxicidade CrônicaRESUMO
Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed.
Assuntos
Química Farmacêutica/métodos , Quinolonas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/farmacologia , Desenho de Fármacos , Genótipo , Hepacivirus/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Ligação Proteica , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis and optimisation of HCV NS5B polymerase inhibitors with improved potency versus the existing compound 1 is described. Substitution in the benzothiadiazine portion of the molecule, furnishing improvement in potency in the high protein Replicon assay, is highlighted, culminating in the discovery of 12h, a highly potent oxyacetamide derivative.
Assuntos
Antivirais/síntese química , Benzotiadiazinas/química , Química Farmacêutica/métodos , Hepacivirus/enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/farmacologia , Benzotiadiazinas/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
Assuntos
Antivirais/síntese química , Benzotiadiazinas/síntese química , Hepacivirus/enzimologia , Quinolonas/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Tiadiazinas/síntese química , Animais , Antivirais/química , Antivirais/farmacologia , Benzotiadiazinas/química , Benzotiadiazinas/farmacologia , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Linhagem Celular , Cristalografia por Raios X , Cães , Genótipo , Meia-Vida , Hepacivirus/genética , Macaca fascicularis , Modelos Moleculares , Estrutura Molecular , Mutação , Ligação Proteica , Quinolonas/química , Quinolonas/farmacologia , RNA Polimerase Dependente de RNA/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiadiazinas/química , Tiadiazinas/farmacologiaRESUMO
[reaction: see text] An efficient two-pot, asymmetric synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available alpha-amino acids or esters, reductive amination followed by a novel one-pot amide bond formation/Dieckmann cyclization provided the desired products in high yield and optical purity. An analogous solid-phase approach to the same targets is also presented. These compounds were found to be potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacologia , Hepacivirus/efeitos dos fármacos , Pirrolidinonas/síntese química , Pirrolidinonas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/química , Benzotiadiazinas/química , Técnicas de Química Combinatória , Ciclização , Hepacivirus/enzimologia , Estrutura Molecular , Pirrolidinonas/químicaRESUMO
Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.