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.

3D-QSAR studies and molecular docking on [5-(4-amino-1H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors

“…Fructose-1,6-bisphosphatase (FBPase, EC 3.1.3.11), a wellknown regulatory enzyme of the hepatic gluconeogenesis (GNG) pathway, catalyzes the irreversible reaction of hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate [1][2][3][4]. GNG is one of the main ways responsible for the excessive hepatic glucose production (HGP) which result in increased fasting blood glucose and postprandial hyperglycemia [5][6][7].…”

“…By using a structure-guided drug design strategy, MB05032 (Fig. 1), one of the most famous AMP mimetics, showed robust glucose lowering activity in animal models as well as patients with T2DM [1,7,9].…”

Discovery of Phosphonic Acid-Containing Desaminobenzimidazoles as Fructose 1,6-Bisphosphatase Inhibitors that are Suitable for Oral Delivery via Prodrugs

“…Recently, a series of phosphonic acid-containing 4-aminobenzimidazoles [1] were reported as adenosine-5'-monophosphate (AMP) mimics. These phosphonic acids function as inhibitors of fructose1,6-bisphosphatase (FBPase), and demonstrated in vivo glucose-lowering activities in rodent models of type 2 diabetes mellitus (T2DM).…”

“…For example, compound 1 ( Figure 1) potently inhibits both human and rat liver FBPase, and elicited rapid glucose-lowering in ZDF rats, however intravenous administration was required. [1,2] Efforts to gain oral bioavailability (OBAV) via prodrugs (e.g. bisPOM ester of compound 1 and cyclic ester prodrug 1a) were not successful.…”

“…It is encouraging to see compound 1.8 showing comparable potency as AMP, despite it does not have a N 1 group, and blocking N 1 -position with a hydrophobic group has been shown to improve FBPase inhibitory potency for the 4-aminobenzimidazole series. [1] Thus, the N 1 -SAR of the desaminobenzimidazole scaffold is investigated, and results are summarized in Table 2.…”