PT  - JOURNAL ARTICLE
AU  - Shibazaki, Toshihide
AU  - Tomae, Masaki
AU  - Ishikawa-Takemura, Yukiko
AU  - Fushimi, Nobuhiko
AU  - Itoh, Fumiaki
AU  - Yamada, Mitsuhiko
AU  - Isaji, Masayuki
TI  - KGA-2727, a Novel Selective Inhibitor of a High-Affinity Sodium Glucose Cotransporter (SGLT1), Exhibits Antidiabetic Efficacy in Rodent Models
AID  - 10.1124/jpet.112.193045
DP  - 2012 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 288--296
VI  - 342
IP  - 2
4099  - http://jpet.aspetjournals.org/content/342/2/288.short
4100  - http://jpet.aspetjournals.org/content/342/2/288.full
SO  - J Pharmacol Exp Ther2012 Aug 01; 342
AB  - 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-1H-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.