Structure-activity relationship (SAR) among prostacyclin (PGI2) analogues

Area of Science:

• Medicinal Chemistry
• Pharmacology

Background:

• Prostacyclin (PGI2) plays a crucial role in cardiovascular regulation.
• Existing PGI2 analogues have limitations in duration of action and biological selectivity.
• There is a need for more stable and selective PGI2 derivatives for therapeutic applications.

Purpose of the Study:

• To synthesize and evaluate novel PGI2 analogues with improved duration of action and/or biological selectivity.
• To chemically stabilize the PGI2 molecule to enhance its resistance to hydrolysis.
• To achieve biological stabilization through modifications of the prostacyclin skeleton.

Main Methods:

• Chemical modification of the PGI2 structure by inserting electron-withdrawing groups (e.g., oxo-, phenyl) adjacent to the enol-ether unit.
• Synthesis of various PGI2 analogues, including 7-oxo-PGI2, 4-oxo-PGI2, and m-interphenylene-2,3,4-trinor-PGI2.
• Elaboration of m-interphenylene-PGI2 series with modifications to the prostaglandin skeleton for biological stabilization.

Main Results:

• Chemically stabilized analogues (e.g., 7-oxo-PGI2) showed increased stability to hydrolysis but a slight decrease in antiaggregatory and hypotensive activities.
• Selectivity between antiaggregatory and hypotensive actions remained largely unchanged with chemical stabilization.
• Biologically stabilized compounds, such as m-interphenylene-2,3,4-trinor-13,14-didehidro-20-methy l-PGI2, demonstrated enhanced selectivity but not a significant increase in duration of action.
• PGI2 and its analogues exhibit 'hit and run' activities, including delayed anti-ischaemic effects.

Conclusions:

• Chemical and biological stabilization strategies offer potential for developing improved PGI2 analogues.
• While stabilization can enhance selectivity, achieving a significant increase in duration of action remains a challenge.
• Further research into PGI2 analogues is warranted, considering their diverse pharmacological effects, including cytoprotective and anti-ischaemic properties.