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

Nobuyuki Yasuda; Tadashi Nagakura; Takashi Inoue; Kazuto Yamazaki; Naruo Katsutani; Osamu Takenaka; Richard Clark; Fumiyoshi Matsuura; Eita Emori; Seiji Yoshikawa; Kazunobu Kira; Hironori Ikuta; Toshimi Okada; Takao Saeki; Osamu Asano; Isao Tanaka

doi:10.1016/j.ejphar.2006.08.011

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

Eur J Pharmacol. 2006 Oct 24;548(1-3):181-7. doi: 10.1016/j.ejphar.2006.08.011. Epub 2006 Aug 16.

Authors

Nobuyuki Yasuda¹, Tadashi Nagakura, Takashi Inoue, Kazuto Yamazaki, Naruo Katsutani, Osamu Takenaka, Richard Clark, Fumiyoshi Matsuura, Eita Emori, Seiji Yoshikawa, Kazunobu Kira, Hironori Ikuta, Toshimi Okada, Takao Saeki, Osamu Asano, Isao Tanaka

Affiliation

¹ Tsukuba Research laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki, 300-2635, Japan. n-yasuda@hhc.eisai.co.jp

PMID: 16973152
DOI: 10.1016/j.ejphar.2006.08.011

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo(4,5-d)pyridazin-4-one tosylate
Blood Glucose
Hypoglycemic Agents
Imidazoles
Protease Inhibitors
Pyridazines
Recombinant Proteins
Tosyl Compounds
Glucagon-Like Peptide 1
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases