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

Since its discovery by Thorp and Waring in 1962, the clofibrate molecule has undergone various modifications. The all-important phenoxy-2-methyl-2-propionic acid chain was preserved, but it seemed reasonable to try and improve pharmacological activity by substituting for the Cl atom a group with different hydrophobic profile. However, none of the phenylketone derivatives produced had satisfactory antilipaemic properties, except for the benzoyl derivative. Grafting on this derivative a Cl atom in position 4 by an original method based on a vinylogy principle, and esterifying with propanol-2 yielded the most active and best tolerated compound: fenofibrate. Fenofibrate resembles clofibrate in that it has the same phenoxy-2-methyl-2-propionic chain but differs from it by the way electrons are distributed, by its lipophilia and by its supple structure, the mobile carbon links between the two rings allowing for spatial changes and facilitating adaptation to receptors. The strong individuality of the molecule is undoubtedly responsible for the significant pharmacokinetic and pharmacological differences between fenofibrate and clofibrate.