Nitric oxide donor-based FFA1 agonists: Design, synthesis and biological evaluation as potential anti-diabetic and...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Endocrinology

Background:

• Cardiovascular complications are highly prevalent in type 2 diabetes mellitus (T2DM), persisting even with early diagnosis or intensive glycemic control.
• There is a critical need for interventions that simultaneously address hyperglycemia and cardiovascular risks in T2DM management.
• Current therapeutic strategies often require multiple agents to manage the multifaceted nature of T2DM and its associated complications.

Purpose of the Study:

• To design and synthesize novel hybrid molecules integrating FFA1 agonist and nitric oxide (NO) donor functionalities.
• To evaluate the dual therapeutic potential of these hybrids for anti-hyperglycemic and anti-thrombotic effects in the context of T2DM.
• To identify lead compounds with enhanced efficacy for potential development as T2DM therapeutics with cardiovascular benefits.

Main Methods:

• Computational modeling, including induced-fit docking, was employed to assess the feasibility of hybrid design.
• In vitro assays were conducted to determine FFA1 agonistic and anti-platelet aggregation activities of the synthesized hybrids.
• In vivo studies, specifically oral glucose tolerance tests in mice, were performed to evaluate hypoglycemic effects.
• The role of NO in mediating anti-platelet effects was confirmed using NO scavengers.

Main Results:

• The induced-fit docking study supported the rational design strategy for hybridizing NO donors with FFA1 agonists.
• Synthesized hybrids demonstrated moderate FFA1 agonistic and anti-platelet aggregation activities, with NO mediating the anti-platelet effects.
• Compound 3 exhibited significant hypoglycemic effects in mice, outperforming the reference drug TAK-875 in an oral glucose tolerance test.

Conclusions:

• Novel hybrid molecules combining FFA1 agonism and NO donation present a viable strategy for dual anti-hyperglycemic and anti-thrombotic therapy.
• Compound 3 shows potent hypoglycemic activity and potential cardiovascular benefits, positioning it as a promising candidate for T2DM treatment.
• Multifunctional agents like compound 3 offer a promising avenue for addressing the complex pathophysiology of T2DM and its cardiovascular sequelae.