ASP4000, a novel, selective, dipeptidyl peptidase 4 inhibitor with antihyperglycemic activity

ASP4000, (2 S)-1-{[(1 R,3 S,4 S,6 R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecar bonitrile hydrochloride, is a novel dipeptidyl peptidase (DPP) 4 inhibitor. In the present study, we characterized the compound as an oral antidiabetic agent both in vitro and in vivo. ASP4000 inhi...

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Published inEuropean journal of pharmacology Vol. 590; no. 1; pp. 444 - 449
Main Authors Tanaka-Amino, Keiko, Matsumoto, Kazumi, Hatakeyama, Yoshifumi, Shima, Ichiro, Takakura, Shoji, Muto, Seitaro
Format Journal Article
LanguageEnglish
Published Amsterdam Elsevier B.V 20.08.2008
Elsevier
Subjects
ASP4000
Biological and medical sciences
Dipeptidyl peptidase 4
Glucagon-like peptide-1
Medical sciences
Pharmacology. Drug treatments
Zucker fa/fa rat
Zucker fa/fa rat
Dipeptidyl peptidase 4
Glucagon-like peptide-1
ASP4000
Rat
Enzyme
Rodentia
Glucagon like peptide 1
Peptidases
Vertebrata
Gastrointestinal hormone
Mammalia
Animal
Dipeptides
Hydrolases
Inhibitor
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Summary:ASP4000, (2 S)-1-{[(1 R,3 S,4 S,6 R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecar bonitrile hydrochloride, is a novel dipeptidyl peptidase (DPP) 4 inhibitor. In the present study, we characterized the compound as an oral antidiabetic agent both in vitro and in vivo. ASP4000 inhibited human recombinant DPP4 with an IC 50 value of 2.25 nM, and the enzyme–kinetic curve indicated that the inhibition type was competitive. In addition, ASP4000 also potently inhibited DPP4 activity in human, rat, dog, and monkey plasma at concentrations of the order of 10 − 9  M, and showed high selectivity against other related enzymes, including DPP8 and DPP9. The antihyperglycemic activity of ASP4000 in vivo was examined using Zucker fa/fa rats, a type 2 diabetes animal model. A single oral administration of ASP4000 at doses of 0.03–1 mg/kg suppressed plasma DPP4 activity, and then reduced the glucose level with increasing the active GLP-1 and insulin levels in oral glucose tolerance test. These results indicate that ASP4000 is a potent, competitive, selective DPP4 inhibitor with antihyperglycemic activity, and could be a promising candidate agent for the treatment of patients with type 2 diabetes.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2008.05.034