Design and synthesis of new potent dipeptidyl peptidase IV inhibitors with enhanced ex vivo duration.
A series of 5beta-methylprolyl-2-cyanopyrrolidine analogs were synthesized and evaluated as DPP-IV inhibitors, and the duration of their ex vivo activity was assessed. Comparison of their potency and duration of action was done among three different species. The mode of binding was investigated, and the effect on the plasma glucose level was evaluated. Structure-activity relationships are also presented.
Kondo
Takashi
T
Minase Research Institute, Ono Pharmaceutical Co. Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. t.kondou@ono.co.jp
Nekado
Takahiro
T
Sugimoto
Isamu
I
Ochi
Kenya
K
Takai
Shigeyuki
S
Kinoshita
Atsushi
A
Tajima
Yohei
Y
Yamamoto
Susumu
S
Kawabata
Kazuhito
K
Nakai
Hisao
H
Toda
Masaaki
M
D000818:Animals; D002855:Chromatography, Thin Layer; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004285:Dogs; D005951:Glucose Tolerance Test; D006801:Humans; D007202:Indicators and Reagents; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010084:Oxidation-Reduction; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4