ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity.

Abstract

Dipeptidyl peptidase (DPP)-IV inhibitors are expected to become a useful new class of antidiabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of ASP8497, (2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate, which is a novel DPP-IV inhibitor. ASP8497 inhibited DPP-IV in plasma from mice, rats, dogs and humans with IC(50) values of 3.86, 2.36, 5.53 and 5.30 nM, respectively. In contrast, ASP8497 did not potently inhibit DPP8 or DPP9 activity (IC(50)>200 nM). Kinetic analysis indicated that ASP8497 inhibits DPP-IV activity in a competitive manner. In streptozotocin-nicotinamide-induced diabetic mice, ASP8497 (3 mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 0.5 and 8.5 h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels. In contrast, ASP8497 (3 and 30 mg/kg) did not cause hypoglycemia in fasted normal mice. Furthermore, administration of exogenous GLP-1 induced significant inhibition of gastric emptying and small intestinal transit rates, but ASP8497 (30 mg/kg) had no significant effects in normal mice. These present preclinical studies indicate that ASP8497 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes.

• Authors: Akiko Matsuyama-Yokono, Atsuo Tahara, Ryosuke Nakano, Yuka Someya, Itsuro Nagase, Masahiko Hayakawa, Masayuki Shibasaki
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 76 Issue 1 Pg. 98-107 (Jul 01 2008) ISSN: 1873-2968 [Electronic] England
• PMID: 18468582 (Publication Type: Journal Article)

Chemical References

• 4-fluoro-1-(((4-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)acetyl)pyrrolidine-2-carbonitrile
• Blood Glucose
• Dipeptidyl-Peptidase IV Inhibitors
• Hypoglycemic Agents
• Insulin
• Piperidines
• Protease Inhibitors
• Pyrrolidines
• Streptozocin

Topics

• Animals
• Blood Glucose (analysis)
• Diabetes Mellitus, Experimental (enzymology)
• Dipeptidyl-Peptidase IV Inhibitors
• Glucose Tolerance Test
• Hypoglycemic Agents (pharmacology)
• Insulin (blood)
• Mice
• Piperidines (pharmacology)
• Protease Inhibitors (pharmacology)
• Pyrrolidines (pharmacology)
• Streptozocin