TY - JOUR T1 - KGA-2727, a novel selective inhibitor of high-affinity sodium glucose cotransporter (SGLT1), exhibits antidiabetic efficacy in rodent models. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.112.193045 SP - jpet.112.193045 AU - Toshihide Shibazaki AU - Masaki Tomae AU - Yukiko Ishikawa-Takemura AU - Nobuhiko Fushimi AU - Fumiaki Itoh AU - Mitsuhiko Yamada AU - Masayuki Isaji Y1 - 2012/01/01 UR - http://jpet.aspetjournals.org/content/early/2012/04/26/jpet.112.193045.abstract N2 - The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed KGA-2727, (3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide), 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 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 also 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 to be a candidate for a novel and useful antidiabetic agent. ER -