title: 7-But-2-ynyl-9-(6-methoxy-pyridin-3-yl)-6-piperazin-1-yl-7,9-dihydro-purin-8-one is a novel competitive and selective inhibitor of dipeptidyl peptidase IV with an antihyperglycemic activity.
abstract: 7-But-2-ynyl-9-(6-methoxy-pyridin-3-yl)-6-piperazin-1-yl-7,9-dihydro-purin-8-one (ER-319711) is a novel dipeptidyl peptidase (DPP)-IV inhibitor discovered in our laboratories. In this study, we have characterized this DPP-IV inhibitor in vitro and in vivo as an antidiabetic agent. The trifluoroacetate salt form of ER-319711, ER-319711-15, inhibited human DPP-IV with an IC(50) value of 0.089 microM, whereas its IC(50) values toward human DPP8 and DPP9 were >100 microM. Inhibition kinetic pattern analysis indicated that ER-319711-15 inhibited DPP-IV in a competitive manner. ER-319711-15 (1 mg/kg) reduced glucose excursion in an oral glucose tolerance test (OGTT) using Zucker fa/fa rats, with significant increases in plasma insulin and active glucagon-like peptide-1 levels. In an OGTT using mice fed a high-fat diet in which ER-319711-15 (0.1-10 mg/kg) was orally administered at 0 h, and glucose was loaded at 0 and 5 h, this compound improved glucose tolerance dose dependently at both 0- and 5-h glucose loading. Next, we compared efficacy of ER-319711-15, E3024, a competitive DPP-IV inhibitor having an imidazopyridazinone structure, or vildagliptin, a slow-binding and long-acting DPP-IV inhibitor, at the same dose, 10 mg/kg, in the same procedures. At the first glucose challenge, all compounds lowered area under the curve (AUC) values of delta blood glucose between 0 and 2 h significantly to the same degree. At the second glucose load, the AUC values between 5 and 7 h were significantly decreased by ER-319711-15 and vildagliptin, but not by E3024. Therefore, ER-319711 might be a potent, competitive, and selective DPP-IV inhibitor with an antihyperglycemic activity.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan. k5-yamazaki@hhc.eisai.co.jp
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yasuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Inoue
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagakura
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kira
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shinoda
authors.forename: Takao
authors.initials: T
authors.lastname: Saeki
authors.forename: Isao
authors.initials: I
authors.lastname: Tanaka
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004041:Dietary Fats; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D018149:Glucose Intolerance / Q000188:drug therapy; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles; D010879:Piperazines / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011759:Pyrrolidines; D051381:Rats; D011924:Rats, Zucker; D014105:Tosyl Compounds / Q000494:pharmacology; D000077597:Vildagliptin
chemical_list: C515375:3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo(4,5-d)pyridazin-4-one tosylate; C515927:7-but-2-ynyl-9-(6-methoxy-pyridin-3-yl)-6-piperazin-1-yl-7,9-dihydro-purin-8-one; D001786:Blood Glucose; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007328:Insulin; D009570:Nitriles; D010879:Piperazines; D011480:Protease Inhibitors; D011687:Purines; D011724:Pyridazines; D011759:Pyrrolidines; D014105:Tosyl Compounds; D052216:Glucagon-Like Peptide 1; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane