KGA-2727, a novel selective inhibitor of a high-affinity sodium glucose cotransporter (SGLT1), exhibits antidiabetic efficacy in rodent models.

Abstract

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.

• Authors: Toshihide Shibazaki, Masaki Tomae, Yukiko Ishikawa-Takemura, Nobuhiko Fushimi, Fumiaki Itoh, Mitsuhiko Yamada, Masayuki Isaji
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 342 Issue 2 Pg. 288-96 (Aug 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 22537769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(3-(4-(3-(glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl)-3-methylphenoxy)propylamino)propionamide
• Glucosides
• Glycated Hemoglobin A
• Hypoglycemic Agents
• Insulin
• Pyrazoles
• SLC5A1 protein, human
• Slc5a1 protein, rat
• Sodium-Glucose Transporter 1
• Glucagon-Like Peptide 1
• Glucose

Topics

• Animals
• Diabetes Mellitus, Experimental (drug therapy, metabolism)
• Glucagon-Like Peptide 1 (metabolism)
• Glucose (metabolism)
• Glucosides (metabolism, pharmacology)
• Glycated Hemoglobin (metabolism)
• Humans
• Hyperglycemia (drug therapy, metabolism)
• Hypoglycemic Agents (chemistry, pharmacology)
• Insulin (metabolism)
• Intestinal Absorption (drug effects)
• Intestine, Small (drug effects, metabolism)
• Islets of Langerhans (drug effects, metabolism)
• Male
• Pyrazoles (pharmacology)
• Rats
• Rats, Wistar
• Rats, Zucker
• Sodium-Glucose Transporter 1 (antagonists & inhibitors, metabolism)