RESUMO
A series of 3-anilino-quinoxalinones has been identified as a new class of glycogen phosphorylase inhibitors. The lead compound 1 was identified through high throughput screening as well as through pharmacophore-based electronic screening. Modifications were made to the scaffold of 1 to produce novel analogues, some of which are 25 times more potent than the lead compound.
Assuntos
Glicogênio Fosforilase/antagonistas & inibidores , Hipoglicemiantes/síntese química , Animais , Glicemia/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Hipoglicemiantes/farmacocinética , Concentração Inibidora 50 , Camundongos , Camundongos Obesos , Quinoxalinas , Relação Estrutura-AtividadeRESUMO
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 strategy for stereocontrolled syntheses of furanoside type of natural products is developed for a glycosyl aryl ether. This strategy resolves the issue of low diastereoselectivity typical of normal glycosidation methods for furanosides. All the stereochemistry ultimately derives from a desymmetrization of a 2,5-diacyloxy-2,5-dihydrofuran using Pd catalyzed asymmetric allylic alkylation which sets both the absolute stereochemistry and 1,4-relative stereochemistry. Diastereo-controlled elaboration of the 3,4-double bond then completes the synthesis. A new conjunctive reagent, 1-nitro-1-phenylsulfonyl-ethane, is developed to serve as an acyl anion equivalent. The utility of a phenol as a nucleophile in the Pd catalyzed glycosylation is demonstrated. From this strategy emerged a short, practical synthesis of C-2-epi-hygromycin A.
