RESUMO
Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50â¯=â¯45â¯nM), and excellent potency at SGLT2 (IC50â¯=â¯1â¯nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (Fâ¯=â¯78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24â¯h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome.
Assuntos
Derivados de Benzeno/farmacologia , Ciclobutanos/farmacologia , Glicosídeos/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose , Administração Oral , Animais , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/química , Ciclobutanos/administração & dosagem , Ciclobutanos/química , Cães , Relação Dose-Resposta a Droga , Glicosídeos/administração & dosagem , Glicosídeos/química , Haplorrinos , Humanos , Camundongos , Estrutura Molecular , Ratos , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
Replacement of the methyl-thiazole moiety of GW501516 (a PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. A structure-activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARalpha/delta dual agonist. Compound 40 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists, and the potential usage for the treatment of metabolic syndrome.
Assuntos
PPAR alfa/agonistas , PPAR delta/agonistas , Tiadiazóis/química , Tiadiazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Regulação da Expressão Gênica/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Camundongos , Tiadiazóis/síntese química , Tiadiazóis/farmacocinética , Ativação TranscricionalRESUMO
A series of aminoindane derivatives were synthesized and shown to be potent PPARalpha agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARalpha activation and PPARalpha mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague-Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice.