RESUMO
The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aß40 levels upon subcutaneous and oral administration to rats.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/uso terapêutico , Ácido Aspártico Endopeptidases/uso terapêutico , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Desenho de Fármacos , Descoberta de Drogas , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aß following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Anticonvulsivantes/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Hidantoínas/síntese química , Administração Oral , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Anticonvulsivantes/farmacologia , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Hidantoínas/farmacologia , Modelos Moleculares , Ligação Proteica , Ratos , Ratos Sprague-DawleyRESUMO
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aß(42) in various animal models.
Assuntos
Amidinas/síntese química , Secretases da Proteína Precursora do Amiloide/metabolismo , Oxidiazóis/síntese química , Oxazinas/síntese química , Amidinas/farmacocinética , Amidinas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Cães , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Oxazinas/farmacocinética , Oxazinas/farmacologia , Fragmentos de Peptídeos/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
MDM2 is an important negative regulator of the tumor suppressor protein p53 which regulates the expression of many genes including MDM2. The delicate balance of this autoregulatory loop is crucial for the maintenance of the genome and control of the cell cycle and apoptosis. MDM2 hyperactivity, due to amplification/overexpression or mutational inactivation of the ARF locus, inhibits the function of wild-type p53 and can lead to the development of a wide variety of cancers. Thus, the development of anti-MDM2 therapies may restore normal p53 function in tumor cells and induce growth suppression and apoptosis. We report here a novel high-throughput fluorescence polarization binding assay and its application in rank ordering small-molecule inhibitors that block the binding of MDM2 to a p53-derived fluorescent peptide.
Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Polarização de Fluorescência , Proteínas Nucleares/química , Peptídeos/química , Proteínas Proto-Oncogênicas/química , Proteína Supressora de Tumor p53/química , Ciclo Celular/fisiologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2Assuntos
Antipsicóticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Piperazinas/administração & dosagem , Tiazóis/administração & dosagem , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno Bipolar/complicações , Criança , Quimioterapia Combinada , Humanos , Masculino , OlanzapinaAssuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Piperazinas/uso terapêutico , Quinolonas/uso terapêutico , Adolescente , Antipsicóticos/administração & dosagem , Aripiprazol , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Piperazinas/administração & dosagem , Quinolonas/administração & dosagemRESUMO
The lambda-dynamics method was used to calculate the relative binding free energies of inhibitors to the hepatitis C virus (HCV) protease. A total of seven HCV protease p-side product inhibitors were used in this study. The inhibitors are 6-mer peptides spanning P6-P1 (Ac-Asp-d-Glu-Leu-Ile-Cha-P1-CO(2)H). For this protein, S1 is a major hydrophobic pocket for binding. Binding of various residues to this pocket was investigated through free energy simulations and experimental inhibition constants. Several 300 ps lambda-dynamics simulations in explicit solvent were performed. The relative binding free energy was estimated from these simulations. From a single simulation, the inhibitors can be correctly classified into highly potent and weakly potent groups. The multiple simulations give an accurate rank ordering of inhibitor potency; computed and experimental binding free energies agree with 0.6 kcal/mol for five of the seven inhibitors. In addition, free energy perturbation (FEP) calculations were carried out to validate the results from lambda-dynamics. A total of 6 ligand pairs were compared. For each pair, 5-11 windows were used to map one ligand to the other. The cumulative simulation time was over 2 ns for each ligand pair. For four of the six ligand pairs, the lambda-dynamics free energy difference fits better than the FEP difference to the experimental value. The fact that the lambda-dynamics method achieved similar results in only a fraction of the total simulation time for FEP further demonstrates the robustness of the lambda-dynamics method.
Assuntos
Endopeptidases/química , Hepacivirus/química , Oligopeptídeos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/química , Ligação Proteica , TermodinâmicaAssuntos
Acetatos/administração & dosagem , Aminas , Ácidos Cicloexanocarboxílicos , Transtornos Fóbicos/tratamento farmacológico , Ácido gama-Aminobutírico , Adolescente , Comorbidade , Cicloexanóis/administração & dosagem , Quimioterapia Combinada , Feminino , Gabapentina , Humanos , Hidroxizina/administração & dosagem , Masculino , Transtornos Mentais/complicações , Transtornos Mentais/tratamento farmacológico , Transtornos Fóbicos/complicações , Resultado do Tratamento , Cloridrato de VenlafaxinaRESUMO
Truncation and substitution SAR studies of azapeptide-based inhibitors of the Hepatitis C virus (HCV) NS3 serine protease have been performed. These azapeptides were designed from the HCV polyprotein's NS5A-NS5B trans cleavage junction and contained an azaamino acid residue at the P1 position. These azapeptides exhibited predominantly non-acylating, competitive inhibition, contrary to classical azapeptides.