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.
Iino
Tomoharu
T
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan. tomoharu_iino@merck.com
Hashimoto
Noriaki
N
Sasaki
Kaori
K
Ohyama
Sumika
S
Yoshimoto
Riki
R
Hosaka
Hideka
H
Hasegawa
Takuro
T
Chiba
Masato
M
Nagata
Yasufumi
Y
Eiki
Jun-ichi
J
Nishimura
Teruyuki
T
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