Boucherle A
Nouv Presse Med. 1980 Dec 22;9(49):3721-3.
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.
自1962年索普和韦林发现氯贝丁酯分子以来，该分子经历了各种修饰。至关重要的苯氧基 - 2 - 甲基 - 2 - 丙酸链得以保留，但通过用具有不同疏水特性的基团取代氯原子来尝试提高药理活性似乎是合理的。然而，除了苯甲酰衍生物外，所制备的苯基酮衍生物均没有令人满意的降血脂特性。通过基于乙烯酮原理的一种原始方法在该衍生物的4位接上一个氯原子，并与2 - 丙醇酯化，得到了活性最高且耐受性最佳的化合物：非诺贝特。非诺贝特与氯贝丁酯相似之处在于它具有相同的苯氧基 - 2 - 甲基 - 2 - 丙酸链，但在电子分布方式、亲脂性及其灵活的结构方面与之不同，两个环之间可移动的碳链允许空间变化并便于与受体适配。该分子的强烈个性无疑是造成非诺贝特与氯贝丁酯之间显著药代动力学和药理学差异的原因。
