title: Design and synthesis of long-acting inhibitors of dipeptidyl peptidase IV.
abstract: 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.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co. Ltd, 3-1-1 Sakurai, Shimamoto-Cho, Mishima-Gun, 618-8585 Osaka, Japan. t.kondou@ono.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.forename: Isamu
authors.initials: I
authors.lastname: Sugimoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nekado
authors.forename: Kenya
authors.initials: K
authors.lastname: Ochi
authors.forename: Tazumi
authors.initials: T
authors.lastname: Ohtani
authors.forename: Yohei
authors.initials: Y
authors.lastname: Tajima
authors.forename: Susumu
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawabata
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: 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
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D012996:Solutions; D005966:Glucuronidase