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1.
Bioorg Med Chem Lett ; 25(17): 3488-94, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26212776

RESUMO

Synthesis and SAR studies of novel triazolobenzazepinones as gamma secretase modulators (GSMs) are presented in this communication. Starting from our azepinone leads, optimization studies toward improving central lowering of Aß42 led to the discovery of novel benzo-fused azepinones. Several benzazepinones were profiled in vivo and found to lower brain Aß42 levels in Sprague Dawley rats and transgenic APP-YAC mice in a dose-dependent manner after a single oral dose. Compound 34 was further progressed into a pilot study in our cisterna-magna-ported rhesus monkey model, where we observed robust lowering of CSF Aß42 levels.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Descoberta de Drogas , Macaca mulatta , Camundongos , Camundongos Transgênicos , Ratos , Ratos Sprague-Dawley
2.
J Med Chem ; 64(21): 16213-16241, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34714078

RESUMO

Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.


Assuntos
Imidazóis/química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Piridinas/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismo
3.
J Biomol Screen ; 14(6): 636-42, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19531664

RESUMO

Fatty acid synthase (FAS), an essential enzyme for de novo lipogenesis, has been implicated in a number of disease states, including obesity, dyslipidemia, and cancer. To identify small-molecule inhibitors of FAS, the authors developed a bead-based scintillation proximity assay (SPA) to detect the fatty acid products of FAS enzymatic activity. This homogeneous SPA assay discriminates between a radiolabeled hydrophilic substrate of FAS (acetyl-coenzyme A) and the labeled lipophilic products of FAS (fatty acids), generating signal only when labeled fatty acids are present. The assay requires a single addition of unmodified polystyrene imaging SPA beads and can be miniaturized to 384- or 1536-well density with appropriate assay statistics for high-throughput screening. High-potency FAS inhibitors were used to compare the sensitivity of the SPA bead assay with previously described assays that measure FAS reaction intermediates (CoA-SH and NADP+). The advantages and disadvantages of these different FAS assays in small-molecule inhibitor discovery are discussed.


Assuntos
Bioensaio/métodos , Ácido Graxo Sintases/metabolismo , Acetilcoenzima A/metabolismo , Linhagem Celular , Ácido Graxo Sintases/antagonistas & inibidores , Humanos , NADP/metabolismo , Palmitatos/metabolismo , Transdução de Sinais , Fatores de Tempo , Titulometria
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