RESUMEN
Recent studies have demonstrated that selective 5-HT(1F) receptor agonists inhibit neurogenic dural inflammation, a model of migraine headache, indicating that these compounds may be effective therapies for the treatment of migraine pain. This communication describes the synthesis and discovery of a novel compound, N-[3-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl]-4-fluorobenzamide (4), which possesses high binding affinity and selectivity at the 5-HT(1F) receptor relative to more than 40 other serotonergic and nonserotonergic receptors examined.
Asunto(s)
Benzamidas/síntesis química , Indoles/síntesis química , Trastornos Migrañosos/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/síntesis química , Animales , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacología , Línea Celular , Duramadre/efectos de los fármacos , Cobayas , Humanos , Técnicas In Vitro , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Inflamación , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Conejos , Ratas , Receptores de Neurotransmisores/metabolismo , Receptores de Serotonina/metabolismo , Vena Safena/efectos de los fármacos , Vena Safena/fisiología , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-Actividad , Receptor de Serotonina 5-HT1FRESUMEN
Solution-phase, parallel-synthesis techniques were used to optimize a series of nonbasic NK-1 antagonists, resulting in the identification of (R)-26, an orally bioavailable compound with subnanomolar potency.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Relación Estructura-ActividadRESUMEN
Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl ether and phenol-amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans. AG1343 (Viracept) has recently been approved for marketing for the treatment of AIDS.