RESUMO
Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.
Assuntos
Glicosídeos/química , Hipoglicemiantes/química , Inibidores do Transportador 2 de Sódio-Glicose , Compostos de Espiro/química , Animais , Ciclização , Glicosídeos/síntese química , Glicosídeos/farmacocinética , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Masculino , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio/metabolismoRESUMO
Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.