title: Antihyperglycemic effects of ASP8497 in streptozotocin-nicotinamide induced diabetic rats: comparison with other dipeptidyl peptidase-IV inhibitors.
abstract: (2S,4S)-4-Fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate (ASP8497) is a novel dipeptidyl peptidase (DPP)-IV inhibitor. In this study, we investigated the antidiabetic potency, mechanism, and duration of action of ASP8497 both in vitro and in vivo, and compared it with the DPP-IV inhibitors vildagliptin, sitagliptin, and saxagliptin. ASP8497 inhibited rat plasma DPP-IV activity in vitro with an IC(50) value of 2.96 nmol/l, while those for vildagliptin, sitagliptin, and saxagliptin were 2.12, 8.98, and 2.00 nmol/l, respectively. In rats that had streptozotocin-nicotinamide-induced, mildly diabetes, oral administration of ASP8497 dose-dependently and sustainably inhibited plasma DPP-IV activity. In addition, ASP8497 dose-dependently and significantly improved glucose tolerance with a concomitant increase in plasma glucagon-like peptide 1 (GLP-1) and insulin levels at both 0.5 h and 8 h after dosing. The order of both potency and duration of action for plasma DPP-IV inhibition and glucose tolerance improvement was as follows: saxagliptin > ASP8497 = vildagliptin = sitagliptin. These results suggest that ASP8497 exerts a potent and long-acting DPP-IV inhibitory effect and improves glucose tolerance through glucose-dependent insulinotropic action via elevation of the GLP-1 level in streptozotocin-nicotinamide-induced mildly diabetic rats. This compound is expected to be useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 5-2-3, Toukoudai, Tuskuba, Ibaraki 300-2698, Japan. atsuo.tahara@jp.astellas.com
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.forename: Akiko
authors.initials: A
authors.lastname: Matsuyama-Yokono
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nakano
authors.forename: Yuka
authors.initials: Y
authors.lastname: Someya
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000097:blood; D008297:Male; D009536:Niacinamide; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013997:Time Factors
chemical_list: C530746:4-fluoro-1-(((4-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)acetyl)pyrrolidine-2-carbonitrile; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; D011759:Pyrrolidines; D009536:Niacinamide; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1