[Fenofibrate: chemical development and differences with clofibrate (author's transl)]

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• The clofibrate molecule, discovered in 1962, served as a basis for developing improved lipid-lowering agents.
• Modifications focused on altering the hydrophobic profile of substituents while retaining the core phenoxy-2-methyl-2-propionic acid chain.

Purpose of the Study:

• To synthesize and evaluate novel clofibrate derivatives for enhanced antilipaemic properties.
• To identify a derivative with superior pharmacological activity and tolerability compared to existing compounds.

Main Methods:

• Systematic chemical modification of the clofibrate structure, focusing on phenyl ring substitutions.
• Synthesis of phenylketone derivatives and evaluation of their antilipaemic effects.
• Introduction of a chlorine atom at position 4 via a vinylogy-based method and esterification.

Main Results:

• Most phenylketone derivatives lacked satisfactory antilipaemic activity, with the benzoyl derivative showing some promise.
• Fenofibrate, synthesized through a novel method, emerged as the most potent and well-tolerated compound.
• Fenofibrate exhibits differences in electron distribution, lipophilia, and structural flexibility compared to clofibrate.

Conclusions:

• Fenofibrate represents a significant advancement over clofibrate due to its unique molecular structure.
• The distinct pharmacokinetic and pharmacological profiles of fenofibrate are attributed to its molecular individuality.