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
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.
Assuntos
Isoxazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/química , Amidas/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Isoxazóis/síntese química , Isoxazóis/uso terapêutico , Dor/tratamento farmacológico , Ratos , Canais de Cátion TRPV/metabolismoRESUMO
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.
