Third-Generation CD73 Inhibitors Based on a 4,6-Disubstituted-2-Thiopyridine Scaffold

Area of Science:

• Medicinal Chemistry
• Immunology
• Biochemistry

Background:

• Ecto-5'-nucleotidase (CD73) is a key enzyme in purinergic signaling, often targeted in immune modulation.
• T-cell proliferation is crucial for immune responses and can be modulated by CD73 activity.
• Developing novel CD73 inhibitors is of interest for therapeutic interventions.

Purpose of the Study:

• To synthesize and evaluate novel 4,6-disubstituted-2-thiopyridine derivatives as potential CD73 inhibitors.
• To investigate the structure-activity relationships of these derivatives.
• To assess their impact on T-cell proliferation and potential off-target effects.

Main Methods:

• Synthesis of approximately ninety 4,6-disubstituted-2-thiopyridine derivatives.
• Functional assay on immune cells to measure T-cell proliferation inhibition.
• Inhibition assays on human adenosine A2A receptor (hA2A) in HEK-293 cells.

Main Results:

• Several thiopyridine derivatives were synthesized using efficient one- or two-step procedures.
• Compounds 4 9ab and 4 9ai demonstrated significant antagonism of T-cell proliferation inhibition at 100 μM and 10 μM concentrations.
• These active compounds also exhibited moderate inhibition of the hA2A receptor in the micromolar range.

Conclusions:

• The synthesized 4,6-disubstituted-2-thiopyridine derivatives show promise as CD73 inhibitors.
• Compounds 4 9ab and 4 9ai possess dual activity, inhibiting CD73 and moderately affecting the hA2A receptor.
• Further optimization could lead to more selective and potent inhibitors with reduced molecular size and lipophilicity.