RESUMO
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.
Assuntos
Cicloexanóis/química , Isoxazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Amidas/química , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Capsaicina/toxicidade , Cicloexanóis/farmacocinética , Cicloexanóis/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
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
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.