Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group.
A series of (4beta-substituted)-L-prolylpyrrolidine analogs lacking the electrophilic nitrile function were synthesized and their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and duration of ex vivo activity were evaluated. Structural optimization of a N-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine analog 8, which was found by high-speed analog synthesis, was carried out to improve the potency and duration of action. A representative compound 26 was evaluated to assess its effect on the plasma glucose level after the oGTT (oral glucose tolerance test) in normal rats. Structure-activity relationships (SAR) are also presented.
Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. t.kondou@ono.co.jp
Takashi
T
Kondo
Takahiro
T
Nekado
Isamu
I
Sugimoto
Kenya
K
Ochi
Shigeyuki
S
Takai
Atsushi
A
Kinoshita
Akira
A
Hatayama
Susumu
S
Yamamoto
Katsuya
K
Kishikawa
Hisao
H
Nakai
Masaaki
M
Toda
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D005951:Glucose Tolerance Test; D009570:Nitriles; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines