RESUMO
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.
Assuntos
Desenho de Fármacos , Indóis/síntese química , Neuralgia/tratamento farmacológico , Oxidiazóis/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Células CACO-2 , Humanos , Indóis/química , Indóis/farmacocinética , Camundongos , Oxidiazóis/química , Oxidiazóis/farmacocinética , RatosRESUMO
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.
Assuntos
Compostos Heterocíclicos/química , Indóis/química , Receptor CB1 de Canabinoide/agonistas , Tiazóis/química , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Camundongos , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
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.
Assuntos
Compostos Heterocíclicos/farmacocinética , Receptor CB1 de Canabinoide/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Descoberta de Drogas , Compostos Heterocíclicos/administração & dosagem , RatosRESUMO
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.
