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

• Published in: European journal of pharmacology Vol. 548; no. 1-3; p. 181
• Main Authors: Yasuda, Nobuyuki, Nagakura, Tadashi, Inoue, Takashi, Yamazaki, Kazuto, Katsutani, Naruo, Takenaka, Osamu, Clark, Richard, Matsuura, Fumiyoshi, Emori, Eita, Yoshikawa, Seiji, Kira, Kazunobu, Ikuta, Hironori, Okada, Toshimi, Saeki, Takao, Asano, Osamu, Tanaka, Isao
• Format: Journal Article
• Language: English
• Published: Netherlands 24.10.2006
• Subjects: Animals; Blood Glucose - analysis; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - blood; Dogs; Female; Glucagon-Like Peptide 1 - blood; Humans; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - toxicity; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Imidazoles - toxicity; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - pathology; Male; Mice; No-Observed-Adverse-Effect Level; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Protease Inhibitors - toxicity; Pyridazines - pharmacokinetics; Pyridazines - pharmacology; Pyridazines - toxicity; Rats; Rats, Sprague-Dawley; Rats, Wistar; Rats, Zucker; Recombinant Proteins - metabolism; Tosyl Compounds - pharmacokinetics; Tosyl Compounds - pharmacology; Tosyl Compounds - toxicity
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2006.08.011

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.