RESUMEN
A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.
Asunto(s)
Adamantano/análogos & derivados , Amidohidrolasas/antagonistas & inhibidores , Antiinflamatorios/química , Cannabinoides/química , Inhibidores Enzimáticos/química , Isoxazoles/química , Receptor Cannabinoide CB2/agonistas , Adamantano/química , Adamantano/farmacología , Adamantano/uso terapéutico , Amidohidrolasas/metabolismo , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Peso Corporal/efectos de los fármacos , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Colitis/tratamiento farmacológico , Colitis/patología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Isoxazoles/farmacología , Isoxazoles/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
Recent investigations showed that anandamide, the main endogenous ligand of CB1 and CB2 cannabinoid receptors, possesses analgesic, antidepressant and anti-inflammatory effects. In the perspective to treat inflammatory bowel disease (IBD), our approach was to develop new selective CB2 receptor agonists without psychotropic side effects associated to CB1 receptors. In this purpose, a new series of 3-carboxamido-5-aryl-isoxazoles, never described previously as CB2 receptor agonists, was designed, synthesized and evaluated for their biological activity. The pharmacological results have identified great selective CB2 agonists with in vivo anti-inflammatory activity in a DSS-induced acute colitis mouse model.
Asunto(s)
Antiinflamatorios/uso terapéutico , Colitis/tratamiento farmacológico , Isoxazoles/química , Receptor Cannabinoide CB2/agonistas , Animales , Antiinflamatorios/química , Antiinflamatorios/toxicidad , Proliferación Celular/efectos de los fármacos , Colitis/inducido químicamente , Colitis/patología , Sulfato de Dextran/toxicidad , Células HT29 , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Isoxazoles/uso terapéutico , Isoxazoles/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Further on to our earlier work on the 4-oxo-1,4-dihydropyridine, we describe herein our strategy to get access to potent selective CB2 receptor agonists. Thus, we designed and synthesized 29 compounds, evaluated on both hCB1 and hCB2 cannabinoid receptors, and assessed 11 of them in the TNBS-induced colitis model in mice. Compound 48 was found to be the most efficient of our series, exhibiting an exquisite protection against experimental colitis, superior to the one observed after treatment with Pentasa.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/síntesis química , Antiinflamatorios no Esteroideos/síntesis química , Colitis/prevención & control , Piridinas/síntesis química , Receptor Cannabinoide CB2/agonistas , Adamantano/química , Adamantano/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Unión Competitiva , Proteínas Sanguíneas/metabolismo , Células CHO , Colitis/inducido químicamente , Colitis/patología , Cricetinae , Cricetulus , Humanos , Absorción Intestinal , Ligandos , Ratones , Microsomas Hepáticos/metabolismo , Unión Proteica , Piridinas/química , Piridinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Ácido TrinitrobencenosulfónicoRESUMEN
Growing evidence suggests a role for the endocannabinoid (EC) system, in intestinal inflammation and compounds inhibiting anandamide degradation offer a promising therapeutic option for the treatment of inflammatory bowel diseases. In this paper, we report the first series of carboxamides derivatives possessing FAAH inhibitory activities. Among them, compound 39 displayed significant inhibitory FAAH activity (IC(50)=0.088 µM) and reduced colitis induced by intrarectal administration of TNBS.
Asunto(s)
Amidohidrolasas/química , Colitis/prevención & control , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isoxazoles/química , Isoxazoles/farmacología , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Animales , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura MolecularRESUMEN
Growing evidence shows that CB(2) receptor is an attractive therapeutic target. Starting from a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide as selective CB(2) agonists, we describe here the medicinal chemistry approach leading to the development of CB(2) receptor inverse agonists with a 4-oxo-1,4-dihydropyridine scaffold. The compounds reported here show high affinity and potency at the CB(2) receptor while showing only modest affinity for the centrally expressed CB(1) cannabinoid receptor. Further, we found that the functionality of this series is controlled by its C-6 substituent because agonists bear a methyl or a tert-butyl group and inverse agonists, a phenyl or 4-chlorophenyl group, respectively. Finally, in silico studies suggest that the C-6 substituent could modulate the conformation of W6.48 known to be critical in GPCR activation.