Metabolic activation of N-thiazol-2-yl benzamide as glucokinase activators: Impacts of glutathione trapping on covalent binding.
Glucokinase activators (GKAs) are currently under investigation as potential antidiabetic agents by many pharmaceutical companies. Most of GKAs reported previously possess N-aminothiazol-2-yl amide moiety in their structures because the aminothiazole moiety interacts with glucokinase (GK) and shows strong GK activation. During the development of N-aminothiazol-2-yl amide derivatives, we identified a bioactivation and metabolic liability of 2-aminothizole substructure of GKA 3 by assessing covalent binding, metabolites in liver microsomes and glutathione (GSH) trap assay.
Iino
Tomoharu
T
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Japan. tomoharu_iino@merck.com
Hashimoto
Noriaki
N
Hasegawa
Takuro
T
Chiba
Masato
M
Eiki
Jun-Ichi
J
Nishimura
Teruyuki
T
D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D004789:Enzyme Activation; D005941:Glucokinase / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013450:Sulfones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D001549:Benzamides; D007004:Hypoglycemic Agents; D013450:Sulfones; D013844:Thiazoles; C037689:benzamide; D005941:Glucokinase; D005978:Glutathione