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KGA-2727, a Novel Selective Inhibitor of a High-Affinity Sodium Glucose Cotransporter (SGLT1), Exhibits Antidiabetic Efficacy in Rodent Models

2012; American Society for Pharmacology and Experimental Therapeutics; Volume: 342; Issue: 2 Linguagem: Inglês

10.1124/jpet.112.193045

1521-0103

Toshihide Shibazaki, Masaki Tomae, Yukiko Ishikawa-Takemura, Nobuhiko Fushimi, Fumiaki Itoh, Mitsuhiko Yamada, Masayuki Isaji,

Diet, Metabolism, and Disease

The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed 3-(3-{4-[3-(β-d-glucopyranosyloxy)-5-isopropyl-1 H -pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide (KGA-2727), which has a pyrazole- O -glucoside structure, as the first selective SGLT1 inhibitor. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs. In a small intestine closed loop absorption test with normal rats, KGA-2727 inhibited the absorption of glucose but not that of fructose. After oral intake of starch along with KGA-2727 in normal rats, the residual content of glucose in the gastrointestinal tract increased. In the oral glucose tolerance test with streptozotocin-induced diabetic rats, KGA-2727 attenuated the elevation of plasma glucose after glucose loading, indicating that KGA-2727 improved postprandial hyperglycemia. In Zucker diabetic fatty (ZDF) rats, chronic treatments with KGA-2727 reduced the levels of plasma glucose and glycated hemoglobin. Furthermore, KGA-2727 preserved glucose-stimulated insulin secretion and reduced urinary glucose excretion with improved morphological changes of pancreatic islets and renal distal tubules in ZDF rats. In addition, the chronic treatment with KGA-2727 increased the level of glucagon-like peptide-1 in the portal vein. Taken together, our data indicate that the selective SGLT1 inhibitor KGA-2727 had antidiabetic efficacy and allow us to propose KGA-2727 as a candidate for a novel and useful antidiabetic agent.