Design, synthesis and biological evaluation of novel imidazopyridines as potential antidiabetic GSK3β inhibitors.
Design, synthesis and biological evaluation of the imidazopyridine analogs as novel GSK3β inhibitors for treatment of type 2 diabetes mellitus are described. Most of the analogs exhibited excellent inhibitory activities (IC50<44 nM) against glycogen synthase kinase 3β (GSK3β). The structure-activity relationship (SAR) of the imidazopyridine analogs and the binding mode of analog 23 in the catalytic domain of GSK3β, based on our X-ray crystallography study, are described. In particular, analog 28, which was selected as a potential drug candidate for treatment of type 2 diabetes mellitus, exhibited excellent GSK3β inhibition, pharmacokinetic profiles and blood glucose lowering effect in mouse.
CrystalGenomics, Inc., 5F, Tower A, Korea Bio Park 694-1, Sampyeong-dong, Bundang-gu Seongnam-si Gyeonggi-do 463-400, Republic of Korea.
Seung-Chul
SC
Lee
Hyun Tae
HT
Kim
Choul-Hong
CH
Park
Do Young
DY
Lee
Ho-Jin
HJ
Chang
Soobong
S
Park
Joong Myung
JM
Cho
Sunggu
S
Ro
Young-Ger
YG
Suh
D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D018360:Crystallography, X-Ray; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D015195:Drug Design; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008861:Microsomes / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007093:Imidazoles; D011725:Pyridines; D038362:Glycogen Synthase Kinase 3