Discovery of potent and orally active tricyclic-based FBPase inhibitors

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Fructose-1,6-bisphosphatase (FBPase) is a key enzyme in gluconeogenesis, making it a potential target for managing hyperglycemia.
• Developing effective FBPase inhibitors requires strategies to enhance cellular uptake and activity.
• Prodrug approaches can improve the pharmacokinetic properties of drug candidates.

Purpose of the Study:

• To design and synthesize novel tricyclic phosphonate prodrugs targeting FBPase.
• To evaluate the efficacy of these prodrugs in inhibiting glucose production in vitro.
• To assess the in vivo effect of the most potent prodrug on blood glucose levels in a primate model.

Main Methods:

• Synthesis of a series of tricyclic phosphonate prodrugs.
• In vitro assays using monkey hepatocytes to measure inhibition of glucose production.
• In vivo studies in fasted cynomolgus monkeys to monitor blood glucose levels after administration of prodrug 15c.

Main Results:

• The synthesized prodrugs demonstrated varying degrees of FBPase inhibition.
• Prodrug 15c exhibited potent inhibition of glucose production in monkey hepatocytes.
• Administration of prodrug 15c led to a significant reduction in blood glucose levels in fasted cynomolgus monkeys.

Conclusions:

• Tricyclic phosphonate prodrugs represent a promising class of FBPase inhibitors.
• Prodrug 15c shows significant potential for the treatment of hyperglycemia.
• Further investigation into the therapeutic application of prodrug 15c is warranted.