Design and synthesis of long-acting inhibitors of dipeptidyl peptidase IV.
A series of (4-substituted prolyl)prolinenitriles were synthesized and evaluated as inhibitors of dipeptidylpeptidase IV (DPP-IV). Among those tested, the 4beta-[4-(hydroxyphenyl)prolyl]prolinenitriles showed a potent inhibitory activity with a long duration of action. Metabolic formation of the corresponding phenol glucuronates was found to contribute to their long duration of action. The activity profiles of the synthesized compounds are reported and structure-activity relationships are also presented.
Kondo
Takashi
T
Minase Research Institute, Ono Pharmaceutical Co. Ltd, 3-1-1 Sakurai, Shimamoto-Cho, Mishima-Gun, 618-8585 Osaka, Japan. t.kondou@ono.co.jp
Sugimoto
Isamu
I
Nekado
Takahiro
T
Ochi
Kenya
K
Ohtani
Tazumi
T
Tajima
Yohei
Y
Yamamoto
Susumu
S
Kawabata
Kazuhito
K
Nakai
Hisao
H
Toda
Masaaki
M
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002855:Chromatography, Thin Layer; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D004355:Drug Stability; D005966:Glucuronidase / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012996:Solutions; D016339:Spectrometry, Mass, Fast Atom Bombardment; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D012996:Solutions; D005966:Glucuronidase