RESUMEN
Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.
Asunto(s)
Compuestos Heterocíclicos/farmacocinética , Receptor Cannabinoide CB1/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Descubrimiento de Drogas , Compuestos Heterocíclicos/administración & dosificación , RatasRESUMEN
Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.
Asunto(s)
Compuestos Heterocíclicos/química , Indoles/química , Receptor Cannabinoide CB1/agonistas , Tiadiazoles/química , Animales , Diseño de Fármacos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacocinética , Indoles/síntesis química , Indoles/farmacocinética , Ratones , Microsomas/metabolismo , Modelos Moleculares , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinéticaRESUMEN
A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel.
Asunto(s)
Bencimidazoles/química , Antagonistas de Narcóticos/química , Piperidinas/química , Animales , Cricetinae , Receptores Opioides/metabolismo , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
The unusual beta-nitronitrile functionality was prepared by a simple one-step hydrocyanation of nitroalkenes. These compounds were shown to be precursors to monoprotected 1,3-diamines and 1,3-amino alcohols through the in situ formation of an alpha-cyano-aldenyde.