RESUMEN
The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH2 to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH2. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over ß-arrestin recruitment. Ex vivo experiments show that the combination of GLP-1(9-36)NH2 and LSN3318839 produces glucose-dependent insulin secretion similar to that of GLP-1(7-36)NH2. Under nutrient-stimulated conditions that release GLP-1, LSN3318839 demonstrates robust glucose lowering in animal models alone or in treatment combination with sitagliptin. From a therapeutic perspective, the biological properties of LSN3318839 support the concept that GLP-1R potentiation is sufficient for reducing hyperglycemia.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Administración Oral , Animales , Glucemia/análisis , Descubrimiento de Drogas , Receptor del Péptido 1 Similar al Glucagón/química , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Ratones , Modelos Moleculares , Ratas Sprague-DawleyRESUMEN
This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Diseño de Fármacos , Hipolipemiantes/síntesis química , Quinolinas/química , Tetrazoles/síntesis química , Animales , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/genética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , HDL-Colesterol/efectos de los fármacos , HDL-Colesterol/metabolismo , Perros , Femenino , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Inyecciones Intravenosas , Masculino , Ratones , Ratones Transgénicos , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tetrazoles/química , Tetrazoles/farmacocinéticaRESUMEN
This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Naftiridinas/farmacología , Animales , HDL-Colesterol , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Naftiridinas/síntesis química , Relación Estructura-ActividadRESUMEN
Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R.
Asunto(s)
Piperazinas/química , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/efectos de los fármacos , Ligandos , Estructura Molecular , Piperazinas/síntesis química , Receptor de Melanocortina Tipo 4/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Replacement of the aryl piperazine moiety in compound 1 with a variety of substituted benzylic piperazines (6) yields compounds that afford melanocortin receptor 4 (MCR4) activity. Analogs with ortho substitution on the aromatic ring afforded the highest affinity. Resolution of the stereocenter of the benzylic piperazine based privileged structure revealed that the R-enantiomer was more active.