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ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity
- Source :
-
Biochemical Pharmacology . Jul2008, Vol. 76 Issue 1, p98-107. 10p. - Publication Year :
- 2008
-
Abstract
- 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 IC50 values of 3.86, 2.36, 5.53 and 5.30nM, respectively. In contrast, ASP8497 did not potently inhibit DPP8 or DPP9 activity (IC50 >200nM). Kinetic analysis indicated that ASP8497 inhibits DPP-IV activity in a competitive manner. In streptozotocin–nicotinamide-induced diabetic mice, ASP8497 (3mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 0.5 and 8.5h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels. In contrast, ASP8497 (3 and 30mg/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 (30mg/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. [Copyright &y& Elsevier]
- Subjects :
- *TREATMENT of diabetes
*PANCREATIC secretions
*HYPOGLYCEMIA
*DIABETES
Subjects
Details
- Language :
- English
- ISSN :
- 00062952
- Volume :
- 76
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Biochemical Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 32731911
- Full Text :
- https://doi.org/10.1016/j.bcp.2008.03.021