title: 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.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, California 92037, USA. qun_dang@merck.com
authors.forename: Qun
authors.initials: Q
authors.lastname: Dang
authors.forename: Srinivas Rao
authors.initials: SR
authors.lastname: Kasibhatla
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Jay
authors.initials: J
authors.lastname: Dare
authors.forename: Frank
authors.initials: F
authors.lastname: Taplin
authors.forename: K Raja
authors.initials: KR
authors.lastname: Reddy
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Scarlato
authors.forename: Tony
authors.initials: T
authors.lastname: Gibson
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Poelje
authors.forename: Scott C
authors.initials: SC
authors.lastname: Potter
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
mesh_terms: 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
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D000249:Adenosine Monophosphate; C031000:benzimidazole; D006597:Fructose-Bisphosphatase