RESUMEN
Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT1F receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone moiety generated potent and more selective 5-HT1F receptor agonists. Focused SAR studies around this central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with both the amide CONH group and the ketone CO group play pivotal roles in affecting the adopted conformation and thus the 5-HT1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT1F receptor agonists.
Asunto(s)
Benzamidas/farmacología , Descubrimiento de Drogas , Piperidinas/farmacología , Receptores de Serotonina 5-HT1/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Benzamidas/síntesis química , Benzamidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Teoría Cuántica , Agonistas del Receptor de Serotonina 5-HT1/síntesis química , Agonistas del Receptor de Serotonina 5-HT1/química , Relación Estructura-ActividadRESUMEN
Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.
Asunto(s)
Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Quinolinas/farmacología , Diseño de Fármacos , Humanos , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
Treatment of an electron-rich benzyl ether with DDQ at ambient temperature followed by addition of a silyl enol ether undergoes a C-C bond-forming reaction to afford 3-alkoxy-3-phenyl-propionyl compound. This is a general reaction and works well with a variety of silyl enol ethers to give carbonyl products in yields ranging from 10 to 85%.