RESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Descubrimiento de Drogas , Macaca mulatta , Ratones , Ratones Transgénicos , Ratas , Ratas Sprague-DawleyRESUMEN
Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aß42 IC(50) in cell-based assays and reduced affinity for the hERG channel.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Transactivadores/metabolismo , Triazoles/farmacología , Amidas/química , Amidas/farmacología , Péptidos beta-Amiloides , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Lactamas , Relación Estructura-Actividad , Regulador Transcripcional ERG , Triazoles/químicaRESUMEN
Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aß42 in Sprague-Dawley rats.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Triazoles/síntesis química , Triazoles/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Triazoles/metabolismoRESUMEN
Synthesis, SAR and evaluation of styrenyl quinazolinones as novel gamma secretase modulators are presented in this communication. Starting from literature and in-house leads we evaluated a range of quinazolinones which showed good modulation of γ-secretase activity.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Quinazolinonas/química , Quinazolinonas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Línea Celular , Humanos , Concentración 50 Inhibidora , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Unión Proteica , Quinazolinonas/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Fragmentos de Péptidos/antagonistas & inhibidores , Purinas/química , Purinas/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Purinas/farmacología , Receptores Notch/metabolismo , Relación Estructura-ActividadRESUMEN
The development of a novel series of piperazinyl pyrimidines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a screening hit provided a series of potent gamma-secretase modulators with >180-fold in vitro selectivity over inhibition of Notch cleavage.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Piperazinas/química , Pirimidinas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/fisiología , Línea Celular Tumoral , Células HeLa , Humanos , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Piperazinas/farmacología , Pirimidinas/farmacologíaRESUMEN
We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.
Asunto(s)
Acetatos/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Flúor/química , Piperidinas/química , Acetatos/síntesis química , Acetatos/farmacocinética , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Compuestos de Diazonio/química , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacocinética , Ratas , Receptores Notch/metabolismoRESUMEN
Inefficient glycosylation caused by defective synthesis of lipid-linked oligosaccharide donor results in multi-systemic syndromes known as congenital disorders of glycosylation type I (CDG-I). Strong loss of function mutations are embryonic lethal, patients with partial losses of function are occasionally born but are very ill, presenting with defects in virtually every tissue. CDG-I clinical expression varies considerably and ranges from very mild to severe, and the underlying cause of the variable clinical features is not yet understood. We postulate that accompanying defects in an individual's genetic background enhance the severity of CDG-I clinical phenotypes. Since so many protein structures and functions are compromised in CDG-I illnesses, the gene products that are dependent on N-linked glycosylation which cause lethality or particular symptoms are difficult to resolve. The power of genetic silencing that is a characteristic of C. elegans has allowed us to systematically dissect the complex glycosylation phenotype observed in CDG-I patients into specific glycan-dependent gene products. To accomplish this, we inhibited glycosylation with a sub-phenotypic dose of tunicamycin, reduced single genes by RNA interference, and then sought loci where the combination caused a synthetic or dramatically enhanced phenotype. This screen has identified genes in C. elegans that require N-linked glycans to function properly as well as candidate gene homologues that may enhance the clinical severity of CDG-I disorders in humans.
Asunto(s)
Caenorhabditis elegans , Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/patología , Mapeo Cromosómico/métodos , Modelos Animales de Enfermedad , Animales , Antibacterianos/farmacología , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Resistencia a Medicamentos/genética , Sitios Genéticos , Glicosilación/efectos de los fármacos , Humanos , Fenotipo , Interferencia de ARN/fisiología , ARN Interferente Pequeño/farmacología , Tunicamicina/farmacologíaRESUMEN
An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and improved physical properties. Dose-dependent efficacy in a mouse HCT116 xenograft model was demonstrated with a phenylglycine SHI-1 analog.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Glicina/análogos & derivados , Inhibidores de Histona Desacetilasas , Fenilalanina/química , Acetilación , Amidas , Animales , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Perros , Canal de Potasio ERG1 , Inhibidores Enzimáticos/farmacocinética , Canales de Potasio Éter-A-Go-Go/metabolismo , Glicina/química , Histona Desacetilasa 1 , Humanos , Macaca mulatta , Ratones , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ongoing clinical studies indicate that inhibitors of Class I and Class II histone deacetylase (HDAC) enzymes show great promise for the treatment of cancer. Zolinza (SAHA, Zolinza) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma. As a part of an ongoing effort to identify novel small molecules to target these important enzymes, we have prepared several classes of amino acid-derived HDAC1 inhibitors. The design rationale and in vitro activity against the HDAC1 enzyme and HCT116 cell line are described in this letter.