RESUMEN
A series of indole-O-glucosides and C-glucosides was synthesized and evaluated in SGLT1 and SGLT2 cell-based functional assays. Compounds 2a and 2o were identified as potent SGLT2 inhibitors and screened in ZDF rats.
Asunto(s)
Glucósidos/química , Glucósidos/farmacología , Indoles/química , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Diabetes Mellitus Experimental/orina , Glucosa/metabolismo , Glucósidos/síntesis química , Estructura Molecular , Ratas , Ratas Zucker , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidoresRESUMEN
A series of benzo-fused heteroaryl-O-glucosides was synthesized and evaluated in SGLT1 and 2 cell-based functional assays. Indole-O-glucoside 10a and benzimidazole-O-glucoside 18 exhibited potent in vitro SGLT2 inhibitory activity.
Asunto(s)
Glucósidos/química , Glucósidos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucósidos/síntesis química , Humanos , Estructura MolecularRESUMEN
A series of glucose conjugates was synthesized and tested for inhibition of SGLT1 and SGLT2. The core structure was derived from compound 1a. Modification of the benzofuran moiety and 4'-substituent of the phenyl ring in compound 1a improved selectivity at SGLT2. Select compounds were compared to 1a in metabolic stability and in vivo efficacy studies.
Asunto(s)
Chalcona/análogos & derivados , Chalcona/síntesis química , Proteínas de Transporte de Monosacáridos/antagonistas & inhibidores , Animales , Células Cultivadas , Chalcona/farmacología , Chalconas , Estabilidad de Medicamentos , Glicosilación , Humanos , Técnicas In Vitro , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Microsomas Hepáticos/metabolismo , Florizina/síntesis química , Florizina/farmacología , Ratas , Ratas Zucker , Transportador 1 de Sodio-Glucosa , Transportador 2 de Sodio-Glucosa , Relación Estructura-ActividadRESUMEN
A series of benzoxazinones has been synthesized and tested for PPARgamma agonist activity. Synthetic approaches were developed to provide either racemic or chiral compounds. In vitro functional potency could be measured through induction of the aP2 gene, a target of PPARgamma. These studies revealed that compounds with large aliphatic chains at the nitrogen of the benzoxazinone were the most potent. Substitution of the chain was tolerated and in many cases enhanced the in vitro potency of the compound. Select compounds were further tested for metabolic stability, oral bioavailability in rats, and efficacy in db/db mice after 11 days of dosing. In vivo analysis with 13 and 57 demonstrated that the series has potential for the treatment of type 2 diabetes.
Asunto(s)
Amidas/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Oxazinas/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Amidas/química , Amidas/farmacología , Animales , Disponibilidad Biológica , Sistema Enzimático del Citocromo P-450/metabolismo , Estabilidad de Medicamentos , Femenino , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Oxazinas/química , Oxazinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of benzoxazinones was synthesized as PPARgamma agonists. The compounds were obtained in seven steps, and SAR was developed by variations to the core shown below. The compounds were tested as functional agonists in the induction of the aP2 gene in preadipocytes, and the most potent compound in the series has an EC(50)=0.51 microM. The potency was further confirmed through a PPAR-Gal4 construct. Efficacy has been demonstrated in the db/db mouse model of hyperglycemia.