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 IC50s < 100 nM. Inhibitor 4.4 emerged as a lead compound based on its potent inhibition of human...

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Published in	Journal of medicinal chemistry Vol. 53; no. 1; pp. 441 - 451
Main Authors	Dang, Qun, Kasibhatla, Srinivas Rao, Xiao, Wei, Liu, Yan, DaRe, Jay, Taplin, Frank, Reddy, K. Raja, Scarlato, Gerard R, Gibson, Tony, van Poelje, Paul D, Potter, Scott C, Erion, Mark D
Format	Journal Article
Language	English
Published	WASHINGTON American Chemical Society 14.01.2010 Amer Chemical Soc
Subjects	Adenosine Monophosphate - chemistry Adenosine Monophosphate - metabolism Animals Benzimidazoles - chemical synthesis Benzimidazoles - chemistry Benzimidazoles - pharmacology Biological and medical sciences Chemistry, Medicinal Diabetes Mellitus, Type 2 - drug therapy Disease Models, Animal Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Fructose-Bisphosphatase - antagonists & inhibitors General and cellular metabolism. Vitamins Humans Life Sciences & Biomedicine Liver - enzymology Medical sciences Molecular Structure Organophosphonates - chemistry Pharmacology & Pharmacy Pharmacology. Drug treatments Rats Rats, Zucker Science & Technology Stereoisomerism Structure-Activity Relationship FRUCTOSE 1,6-BISPHOSPHATASE POTENT HYPERGLYCEMIA ANALOGS PRODRUGS CS-917 BENZOXAZOLE BENZENESULFONAMIDES ALLOSTERIC INHIBITORS DISCOVERY DELIVERY Endocrinopathy Type 2 diabetes Fructose-bisphosphatase Rat Enzyme Rodentia Furan derivatives Phosphonic acids Phosphoric monoester hydrolases Metabolic diseases Esterases In vitro Phosphorus Organic compounds In vivo Vertebrata Hypoglycemic agent Mammalia Structure activity relation Benzimidazole derivatives Animal Hydrolases Inhibitor Fluorine Organic compounds Chemical synthesis
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ISSN	0022-2623 1520-4804 1520-4804
DOI	10.1021/jm901420x

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Summary:	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 IC50s < 100 nM. Inhibitor 4.4 emerged as a lead compound based on its potent inhibition of human liver FBPase (IC50 = 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804 1520-4804
DOI:	10.1021/jm901420x