RESUMEN
Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration.
Asunto(s)
Isoxazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/química , Amidas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Humanos , Isoxazoles/síntesis química , Isoxazoles/uso terapéutico , Dolor/tratamiento farmacológico , Ratas , Canales Catiónicos TRPV/metabolismoRESUMEN
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
Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.
Asunto(s)
Ciclohexanoles/química , Isoxazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Amidas/química , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Capsaicina/toxicidad , Ciclohexanoles/farmacocinética , Ciclohexanoles/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Isoxazoles/farmacocinética , Isoxazoles/uso terapéutico , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.
Asunto(s)
Compuestos Heterocíclicos/química , Indoles/química , Receptor Cannabinoide CB1/agonistas , Tiazoles/química , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacocinética , Ratones , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.