RESUMO
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.
Assuntos
Glucosídeos/química , Glucosídeos/farmacologia , Indóis/química , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Diabetes Mellitus Experimental/urina , Glucose/metabolismo , Glucosídeos/síntese química , Estrutura Molecular , Ratos , Ratos Zucker , Transportador 1 de Glucose-Sódio/antagonistas & inibidoresRESUMO
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.
Assuntos
Glucosídeos/química , Glucosídeos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Glucosídeos/síntese química , Humanos , Estrutura MolecularRESUMO
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.
Assuntos
Chalcona/análogos & derivados , Chalcona/síntese química , Proteínas de Transporte de Monossacarídeos/antagonistas & inibidores , Animais , Células Cultivadas , Chalcona/farmacologia , Chalconas , Estabilidade de Medicamentos , Glicosilação , Humanos , Técnicas In Vitro , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Microssomos Hepáticos/metabolismo , Florizina/síntese química , Florizina/farmacologia , Ratos , Ratos Zucker , Transportador 1 de Glucose-Sódio , Transportador 2 de Glucose-Sódio , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Oxazinas/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Amidas/química , Amidas/farmacologia , Animais , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/metabolismo , Estabilidade de Medicamentos , Feminino , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Oxazinas/química , Oxazinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
