Fructose-1,6-bisphosphatase Inhibitors. 2. Design, synthesis, and structure-activity relationship of a series of phosphonic acid containing benzimidazoles that function as 5'-adenosinemonophosphate (AMP) mimics.
Efforts to enhance the inhibitory potency of the initial purine series of fructose-1,6-bisphosphatase (FBPase) inhibitors led to the discovery of a series of benzimidazole analogues with human FBPase IC(50)s < 100 nM. Inhibitor 4.4 emerged as a lead compound based on its potent inhibition of human liver FBPase (IC(50) = 55 nM) and significant glucose lowering in normal fasted rats. Intravenous administration of 4.4 to Zucker diabetic fatty rats led to rapid and robust glucose lowering, thereby providing the first evidence that FBPase inhibitors could improve glycemia in animal models of type 2 diabetes.
Dang
Qun
Q
Department of Medicinal Chemistry, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, California 92037, USA. qun_dang@merck.com
Kasibhatla
Srinivas Rao
SR
Xiao
Wei
W
Liu
Yan
Y
Dare
Jay
J
Taplin
Frank
F
Reddy
K Raja
KR
Scarlato
Gerard R
GR
Gibson
Tony
T
van Poelje
Paul D
PD
Potter
Scott C
SC
Erion
Mark D
MD
D000249:Adenosine Monophosphate / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors*; D006801:Humans; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry*; D051381:Rats; D011924:Rats, Zucker; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D000249:Adenosine Monophosphate; C031000:benzimidazole; D006597:Fructose-Bisphosphatase