RESUMEN
Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Diamida/química , Inhibidores Enzimáticos/química , Animales , Línea Celular Tumoral , Diacilglicerol O-Acetiltransferasa/metabolismo , Diamida/síntesis química , Diamida/farmacocinética , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Semivida , Humanos , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Apolipoprotein E is a 299-residue lipid carrier protein produced in both the liver and the brain. The protein has three major isoforms denoted apoE2, apoE3, and apoE4 which differ at positions 112 and 158 and which occur at different frequencies in the human population. Genome-wide association studies indicate that the possession of two apoE4 alleles is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). In an attempt to identify a small molecule stabilizer of apoE4 function that may have utility as a therapy for Alzheimer's disease, we carried out an NMR-based fragment screen on the N-terminal domain of apoE4 and identified a benzyl amidine based fragment binder. In addition to NMR, binding was characterized using various other biophysical techniques, and a crystal structure of the bound core was obtained. Core elaboration ultimately yielded a compound that showed activity in an IL-6 and IL-8 cytokine release assay.
Asunto(s)
Apolipoproteína E4/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amidinas/química , Amidinas/metabolismo , Apolipoproteína E4/química , Apolipoproteína E4/genética , Sitios de Unión , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Liposomas/química , Liposomas/metabolismo , Espectroscopía de Resonancia Magnética , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Dominios Proteicos , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Temperatura de TransiciónRESUMEN
The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders associated with hypofunction of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. Herein, we describe the synthesis and biological evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chemical structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compounds derived from iterative structure-activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclinical pharmacokinetics, and manageable DDI and bioactivation liabilities.
Asunto(s)
Encéfalo/efectos de los fármacos , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Pirrolidinas/química , Sulfonamidas/química , Animales , Encéfalo/metabolismo , Técnicas de Química Sintética , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones Endogámicos , Microsomas Hepáticos/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Pirrolidinonas/efectos adversos , Ratas Sprague-Dawley , Relación Estructura-Actividad , XenopusRESUMEN
The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure-activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7 S,8 R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7 S,8 R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED50 of 0.8 mg/kg. All these results suggest (7 S,8 R)-27a and 51b as new GlyT1 inhibitors worthy of further profiling.
Asunto(s)
Encéfalo/efectos de los fármacos , Cromanos/química , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Tetrahidronaftalenos/química , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Unión Competitiva , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Masculino , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Pirrolidinonas/efectos adversos , Ratas Sprague-Dawley , Relación Estructura-Actividad , XenopusRESUMEN
Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.
Asunto(s)
Antibacterianos/síntesis química , Clostridioides difficile/efectos de los fármacos , Enterocolitis Seudomembranosa/tratamiento farmacológico , Tiazoles/síntesis química , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Cricetinae , Cristalografía por Rayos X , Enterococcus/efectos de los fármacos , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/química , Femenino , Masculino , Mesocricetus , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Factor Tu de Elongación Peptídica/antagonistas & inhibidores , Factor Tu de Elongación Peptídica/química , Ratas , Ratas Sprague-Dawley , Solubilidad , Staphylococcus aureus/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/farmacocinética , AguaRESUMEN
4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.