title: E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, is a novel, selective and competitive dipeptidyl peptidase-IV inhibitor.
abstract: Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a useful new class of anti-diabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, which is a novel imidazopyridazinone-derived DPP-IV inhibitor. E3024 inhibited recombinant human and mouse DPP-IV with IC50 values of approximately 100 nM. E3024 inhibited DPP-IV in human, mouse, rat and canine plasma with IC50 values of 140 to 400 nM. In contrast, E3024 did not inhibit DPP-8 or DPP-9 activity. Kinetic analysis indicated that E3024 is a competitive DPP-IV inhibitor. In Zucker fa/fa rats, E3024 (1 mg/kg) reduced glucose excursion after glucose load, with increases in plasma insulin and active glucagon-like peptide-1 levels. In fasted rats, this compound did not cause hypoglycemia. In a rat 4-week toxicological study, no notable changes were found at doses up to 750 mg/kg. The present preclinical studies indicate that E3024 is a novel selective DPP-IV inhibitor with anti-diabetic effects and a good safety profile.
authors.affiliation: Tsukuba Research laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki, 300-2635, Japan. n-yasuda@hhc.eisai.co.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yasuda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagakura
authors.forename: Takashi
authors.initials: T
authors.lastname: Inoue
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Naruo
authors.initials: N
authors.lastname: Katsutani
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.forename: Richard
authors.initials: R
authors.lastname: Clark
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Matsuura
authors.forename: Eita
authors.initials: E
authors.lastname: Emori
authors.forename: Seiji
authors.initials: S
authors.lastname: Yoshikawa
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kira
authors.forename: Hironori
authors.initials: H
authors.lastname: Ikuta
authors.forename: Toshimi
authors.initials: T
authors.lastname: Okada
authors.forename: Takao
authors.initials: T
authors.lastname: Saeki
authors.forename: Osamu
authors.initials: O
authors.lastname: Asano
authors.forename: Isao
authors.initials: I
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000097:blood; D004285:Dogs; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011724:Pyridazines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011924:Rats, Zucker; D011994:Recombinant Proteins / Q000378:metabolism; D014105:Tosyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
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; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007093:Imidazoles; D011480:Protease Inhibitors; D011724:Pyridazines; D011994:Recombinant Proteins; D014105:Tosyl Compounds; D052216:Glucagon-Like Peptide 1; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases