RESUMO
The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.
Assuntos
Sondas Moleculares/farmacologia , Proteínas Nucleares/metabolismo , Quinazolinonas/farmacologia , Sulfonamidas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Ciclo Celular , Cristalografia por Raios X , Humanos , Modelos Moleculares , Sondas Moleculares/síntese química , Estrutura Molecular , Proteínas Nucleares/antagonistas & inibidores , Ligação Proteica , Quinazolinonas/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Interferons/agonistas , Receptor 7 Toll-Like/agonistas , Aldeído Oxidase/metabolismo , Animais , Antivirais/química , Antivirais/farmacocinética , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Hepacivirus/fisiologia , Hepatite C/virologia , Humanos , Injeções Intravenosas , Indutores de Interferon/síntese química , Indutores de Interferon/química , Indutores de Interferon/farmacocinética , Indutores de Interferon/farmacologia , Microssomos Hepáticos/metabolismo , Terapia de Alvo Molecular , Peso Molecular , Purinas/síntese química , Purinas/metabolismo , Ratos , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.
Assuntos
Antivirais/química , Hepacivirus/efeitos dos fármacos , Purinas/química , Infecções por Vírus de RNA/tratamento farmacológico , Receptor 7 Toll-Like/agonistas , Administração Oral , Animais , Antivirais/síntese química , Antivirais/uso terapêutico , Desenho de Fármacos , Camundongos , Modelos Animais , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Receptor 7 Toll-Like/metabolismoRESUMO
The rhodium-catalysed conjugate addition of arylboronic acids to an enantiopure acceptor derived from (R)-S-methylcysteine proceeds under substrate control to provide a range of functionalised phenylalanine derivatives with excellent stereocontrol via a highly diastereoselective protonation.
Assuntos
Aminoácidos/química , Aminoácidos/síntese química , Ácidos Borônicos/química , Ródio/química , Catálise , Cristalografia por Raios X , Modelos Químicos , Oxazolidinonas/química , Prótons , EstereoisomerismoRESUMO
New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
Assuntos
Inibidores da Captação Adrenérgica/química , Norepinefrina , Piperazinas/química , Inibidores Seletivos de Recaptação de Serotonina/química , Incontinência Urinária por Estresse/tratamento farmacológico , Inibidores da Captação Adrenérgica/metabolismo , Inibidores da Captação Adrenérgica/farmacocinética , Animais , Cães , Humanos , Piperazinas/metabolismo , Piperazinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
The appropriate choice of organometallic nucleophile enables the straightforward preparation of different stereoisomers of 2-substituted pyrrolizidinones utilising the rhodium-catalysed 1,4-addition reaction.
RESUMO
The cationic rhodium complex [Rh(cod)2][BF4] effectively catalyses the 1,4-addition of organotrialkoxysilanes to alpha-substituted acrylic esters. The reactions are promoted by heating in an oil-bath or more conveniently in a microwave reactor allowing rapid access to a useful range of functionalised products including 2-alkyl succinates and alpha-amino acid derivatives.
Assuntos
Ésteres/química , Compostos Orgânicos/síntese química , Ródio , Silanos/química , Catálise , Espectroscopia de Ressonância Magnética , Metais , Modelos Moleculares , Conformação Molecular , Naftalimidas/químicaRESUMO
The synthesis and structure-activity relationships of a novel series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake is described. Two compounds possessed comparable in vitro profiles to the dual reuptake inhibitor duloxetine.
Assuntos
Norepinefrina/química , Piperazinas/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/química , Aminas/química , Química Farmacêutica/métodos , Desenho de Fármacos , Cloridrato de Duloxetina , Humanos , Modelos Químicos , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-Atividade , Tiofenos/farmacologiaRESUMO
We report the structure-activity relationships of further analogues in a series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake, that is, with additional substitution of the phenyl rings, or their replacement by heterocycles. The enantiomers of compounds 1 and 2 were also profiled, and possessed drug-like physicochemical properties. In particular, compound (-)-2 lacked potent inhibitory activity against any of the important cytochromes P(450) and high selectivity over a wide range of receptors, which is unusual for a compound that inhibits human amine transporters.