RESUMEN
(3-Tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d] [1,2,4]triazine was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5-containing receptors, which enhances performance in animal models of cognition. The routes of metabolism of this compound in rat, dog, rhesus monkey and human in vitro systems, and in vivo in rat, dog and rhesus monkey have been characterized. The current study demonstrates that both a cytosolic oxidative reaction and cytochrome P450 play important roles in the metabolism of the compound. Chemical inhibition studies showed the oxidation in human cytosol to be catalysed predominantly by aldehyde oxidase rather than the related enzyme, xanthine oxidase. The aldehyde oxidase-mediated metabolites were present in vitro and in vivo in both rat and rhesus monkey, and also in vitro in man. They were absent both in vitro and in vivo in dog.
Asunto(s)
Aldehído Oxidasa/farmacología , Agonistas de Receptores de GABA-A , Receptores de GABA-A/química , Aldehído Oxidasa/química , Animales , Cromatografía Liquida , Citosol/enzimología , Citosol/metabolismo , Perros , Diseño de Fármacos , Humanos , Técnicas In Vitro , Hígado/metabolismo , Macaca mulatta , Espectrometría de Masas , Ratas , Fracciones Subcelulares , Xantina Oxidasa/química , Xantina Oxidasa/metabolismoRESUMEN
The in vivo properties of a series of 2-arylindole NK(1) antagonists have been improved, by modification of the amide substituent. The 1-(2-methoxyphenyl)piperazine amide was identified as a major area of metabolism in the lead compound 1. Replacement of this amine moiety by a 4-benzyl-4-hydroxypiperidine resulted in a compound 18 with reduced clearance and improved central duration of action.
Asunto(s)
Amidas/química , Indoles/farmacocinética , Neuroquinina A/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Cricetinae , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Tasa de Depuración Metabólica , Piperazinas/química , Ratas , Relación Estructura-ActividadRESUMEN
The development of very high affinity, selective, and bioavailable h5-HT(2A) receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT(2A) receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT(2A) receptors, with bioavailability of 80% and half-life of 12 h in rats.