RESUMEN
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.
Asunto(s)
Isoxazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/química , Amidas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Humanos , Isoxazoles/síntesis química , Isoxazoles/uso terapéutico , Dolor/tratamiento farmacológico , Ratas , Canales Catiónicos TRPV/metabolismoRESUMEN
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.
Asunto(s)
Amidas/química , Antihipertensivos/química , Ciclohexanoles/química , Isoxazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacocinética , Ciclohexanoles/síntesis química , Ciclohexanoles/farmacocinética , Hipertermia Inducida , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
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/metabolismoRESUMEN
The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.