RESUMEN
Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.
RESUMEN
A homology model of the nicotinic acid receptor GPR109A was constructed based on the X-ray crystal structure of bovine rhodopsin. An HTS hit was docked into the homology model. Characterization of the binding pocket by a grid-based surface calculation of the docking model suggested that a larger hydrophobic body plus a polar tail would improve interaction between the ligand and the receptor. The designed compounds were synthesized, and showed significantly improved binding affinity and activation of GPR109A.
Asunto(s)
Modelos Moleculares , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , Receptores Acoplados a Proteínas G/agonistas , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología , Sitios de Unión , Técnicas Químicas Combinatorias , Humanos , Estructura Molecular , Niacina/metabolismo , Agonistas Nicotínicos/química , Receptores Nicotínicos , Relación Estructura-Actividad , ortoaminobenzoatos/químicaRESUMEN
Imidazo[1,2-a]pyridyl N-arylpyridazinones were hybridized from the classic pyridinylimidazoles and the more recent dual hydrogen bond acceptors, resulting in a new structural class of selective p38 MAP kinase inhibitors.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Piridazinas/síntesis química , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ratones , Proteínas Quinasas Activadas por Mitógenos/química , Modelos Moleculares , Piridazinas/química , Piridazinas/farmacología , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
A stereocontrolled synthesis of a complex pentacycle embodying the molecular architecture of the cortistatin class of natural products was achieved from the (+)-Hajos-Parrish ketone. The cornerstone of our approach is a hypervalent iodine induced tandem intramolecular oxidative dearomatization and nitrile oxide cycloaddition. The manner in which these ring formations were orchestrated has yielded a rather concise strategy for synthesis.