1.
Bioorg Med Chem Lett
; 21(15): 4652-7, 2011 Aug 01.
Artículo
en Inglés
| MEDLINE
| ID: mdl-21723725
RESUMEN
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/metabolismo
2.
Bioorg Med Chem Lett
; 21(3): 892-8, 2011 Feb 01.
Artículo
en Inglés
| MEDLINE
| ID: mdl-21236666
RESUMEN
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.