RESUMO
Melanin-concentrating hormone (MCH) is a 19 amino acid long peptide found in the brain of animals, including fishes, batrachians, and mammals. MCH is implicated in appetite and/or energy homeostasis. Antagonists at its receptor (MCH-R1) could be major tools (or ultimately drugs) to understand the mechanism of MCH action and to fight the obesity syndrome that is a worldwide societal health problem. Ever since the deorphanisation of the MCH receptor, we cloned, expressed, and characterized the receptor MCH-R1 and started a vast medicinal chemistry program aiming at the discovery of such usable compounds. In the present final work, we describe GPS18169, a pseudopeptide antagonist at the MCH-R1 receptor with an affinity in the nanomolar range and a Ki for its antagonistic effect in the 20 picomolar range. Its metabolic stability is rather ameliorated compared to its initial parent compound, the antagonist S38151. We tested it in an in vivo experiment using high diet mice. GPS18169 was found to be active in limiting the accumulation of adipose tissues and, correlatively, we observed a normalization of the insulin level in the treated animals, while no change in food or water consumption was observed.
Assuntos
Fármacos Antiobesidade/química , Obesidade/tratamento farmacológico , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Tecido Adiposo/efeitos dos fármacos , Alcinos/química , Aminobutiratos/química , Animais , Fármacos Antiobesidade/farmacologia , Apetite/efeitos dos fármacos , Ácido Aspártico/química , Modelos Animais de Doenças , Descoberta de Drogas , Ácido Glutâmico/química , Glicina/análogos & derivados , Glicina/química , Células HEK293 , Hepatócitos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Insulina/metabolismo , Lactamas/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Relação Estrutura-Atividade , Distribuição Tecidual , Triazóis/químicaRESUMO
We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.
Assuntos
Desenho de Fármacos , Piperazina/química , Piperidinas/química , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Cristalografia por Raios X , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Canal de Potássio ERG1/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Piperazina/síntese química , Piperazina/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Plasma membrane calcium ATPases (PMCAs) are a family of transmembrane proteins responsible for the extrusion of cytosolic Ca2+ to the extracellular milieu. They are important players of the calcium homeostasis possibly implicated in some important diseases. The reference inhibitors of PMCA extruding activity are on one hand ortho-vanadate (IC50 in the 30 mM range), and on the other a series of 12- to 20-mer peptides named caloxins (IC50 in the 100 µM scale). As for all integral membrane proteins, biochemistry and pharmacology are difficult to study on isolated and/or purified proteins. Using a series of reference blockers, we assessed a pharmacological window with which we could study the functionality of PMCAs in living cells. Using this system, we screened for alternative versions of caloxins, aiming at shortening the peptide backbone, introducing non-natural amino acids, and overall trying to get a glimpse at the structure-activity relationship between those new peptides and the protein in a cellular context. We describe a short series of equipotent 5-residue long analogues with IC50 in the low µM range.
Assuntos
Cálcio , ATPases Transportadoras de Cálcio da Membrana Plasmática , Cálcio/metabolismo , Membrana Celular/metabolismo , Proteínas de Membrana/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Relação Estrutura-AtividadeRESUMO
Selective and potent inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) have the potential to increase endogenous and therapeutic fibrinolysis and to behave like profibrinolytic agents without the risk of major hemorrhage, since they do not interfere either with platelet activation or with coagulation during blood hemostasis. Therefore, TAFIa inhibitors could be used in at-risk patients for the treatment, prevention, and secondary prevention of stroke, venous thrombosis, and pulmonary embolisms. In this paper, we describe the design, the structure-activity relationship (SAR), and the synthesis of novel, potent, and selective phosphinanes and azaphosphinanes as TAFIa inhibitors. Several highly active azaphosphinanes display attractive properties suitable for further in vivo efficacy studies in thrombosis models.
Assuntos
Compostos Aza/farmacologia , Carboxipeptidase B2/antagonistas & inibidores , Óxidos P-Cíclicos/farmacologia , Fibrinolíticos/farmacologia , Ácidos Fosfínicos/farmacologia , Inibidores de Proteases/farmacologia , Animais , Compostos Aza/síntese química , Compostos Aza/metabolismo , Carboxipeptidase B2/metabolismo , Domínio Catalítico , Óxidos P-Cíclicos/síntese química , Óxidos P-Cíclicos/metabolismo , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/síntese química , Fibrinolíticos/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/metabolismo , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of thieno[3,2-b]pyrroloazepinones derivatives related to Hymenialdisine were prepared and tested for CHK1 inhibitory activity. Nanomolar inhibitions were achieved when electron-withdrawing substituents were introduced at position 3 of the thiophene ring.
Assuntos
Antineoplásicos/síntese química , Azepinas/síntese química , Química Farmacêutica/métodos , Proteínas Quinases/metabolismo , Pirróis/síntese química , Antineoplásicos/farmacologia , Azepinas/farmacologia , Quinase 1 do Ponto de Checagem , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Elétrons , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Pirróis/farmacologia , Relação Estrutura-Atividade , Tiofenos/químicaRESUMO
The 1,5-benzothiazepine-4-one scaffold was earlier shown to provide efficient protease inhibitors. In this contribution, we describe its use in the design of factor VIIa/tissue factor inhibitors. A series containing a scaffold non-substituted on its aryl part led to compound 20 with an IC(50) of 2.16 microM. Following molecular modelling studies of this compound, a second series was prepared, which necessitated the synthesis of protected 7- or 8-substituted 1,5-benzothiazepine-4-one derivatives.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Fator VIIa/antagonistas & inibidores , Tiazepinas/síntese química , Tromboplastina/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos/métodos , Fator VIIa/metabolismo , Humanos , Tiazepinas/administração & dosagem , Tiazepinas/farmacologia , Tromboplastina/metabolismoRESUMO
The synthesis and evaluation of inhibitors of activated protein C (aPC) are reported. This serine protease is partly responsible for the degradation of factor VIIIa, involved in the regulation of bleeding in hemophilia A. Benzamidine-containing derivatives were found to be potent aPC inhibitors, some of them showing selectivity against the procoagulant protease thrombin. Moreover, compound 1 significantly restored the generation of thrombin in hemophiliac plasma.
Assuntos
Benzamidinas/farmacologia , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Proteína C/antagonistas & inibidores , Inibidores de Serina Proteinase/farmacologia , Benzamidinas/química , Fator VIIIa/metabolismo , Humanos , Estrutura Molecular , Peso Molecular , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores , Trombina/biossínteseRESUMO
Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of the tissue type and urokinase type plasminogen activators. High levels of PAI-1 are correlated with an increased risk of thrombotic events and several other pathologies. Despite several compounds with in vitro activity being developed, none of them are currently in clinical use. In this study, we evaluated a novel PAI-1 inhibitor, annonacinone, a natural product from the Annonaceous acetogenins group. Annonacinone was identified in a chromogenic screening assay and was more potent than tiplaxtinin. Annonacinone showed high potency ex vivo on thromboelastography and was able to potentiate the thrombolytic effect of tPA in vivo in a murine model. SDS-PAGE showed that annonacinone inhibited formation of PAI-1/tPA complex via enhancement of the substrate pathway. Mutagenesis and molecular dynamics allowed us to identify annonacinone binding site close to helix D and E and ß-sheets 2A.