RESUMEN
Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
Asunto(s)
Diseño de Fármacos , Indoles/síntesis química , Neuralgia/tratamiento farmacológico , Oxadiazoles/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Células CACO-2 , Humanos , Indoles/química , Indoles/farmacocinética , Ratones , Oxadiazoles/química , Oxadiazoles/farmacocinética , RatasRESUMEN
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
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.