Discovery of novel 2-(pyridine-2-yl)-1H-benzimidazole derivatives as potent glucokinase activators.
The synthesis and structure-activity-relationships (SARs) of novel 2-(pyridine-2-yl)-1H-benzimidazole glucokinase activators are described. Systematic modification of benzimidazole lead 5a identified from a high-throughput screening led to the discovery of a potent and metabolically stable glucokinase activator 16p(R) with greater structural diversity from GKAs reported to date. The compound also demonstrated acute oral glucose lowering efficacy in rat OGTT model.
Ishikawa
Makoto
M
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba 300-2611, Ibaraki, Japan. makoto.ishikawa@mochida.co.jp
Nonoshita
Katsumasa
K
Ogino
Yoshio
Y
Nagae
Yoshikazu
Y
Tsukahara
Daisuke
D
Hosaka
Hideka
H
Maruki
Hiroko
H
Ohyama
Sumika
S
Yoshimoto
Riki
R
Sasaki
Kaori
K
Nagata
Yasufumi
Y
Eiki
Jun-Ichi
J
Nishimura
Teruyuki
T
D000495:Allosteric Site; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D015195:Drug Design; D004789:Enzyme Activation; D005941:Glucokinase / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D008956:Models, Chemical; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D007004:Hypoglycemic Agents; C031000:benzimidazole; D005941:Glucokinase