Structure-activity relationships of 3,5-disubstituted benzamides as glucokinase activators with potent in vivo efficacy.
The optimization of our lead GK activator 2a to 3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide (6g), a potent GK activator with good oral availability, is described, including to uncouple the relationship between potency and hydrophobicity. Following oral administration, this compound exhibited robust glucose lowering in diabetic model rodents.
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan. tomoharu_iino@merck.com
Tomoharu
T
Iino
Noriaki
N
Hashimoto
Kaori
K
Sasaki
Sumika
S
Ohyama
Riki
R
Yoshimoto
Hideka
H
Hosaka
Takuro
T
Hasegawa
Masato
M
Chiba
Yasufumi
Y
Nagata
Jun-ichi
J
Eiki
Teruyuki
T
Nishimura
D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects*; D020536:Enzyme Activators / Q000737:chemistry* / Q000494:pharmacology*; D005941:Glucokinase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
D001549:Benzamides; D020536:Enzyme Activators; D005941:Glucokinase