Applications of fluorine-containing amino acids for drug design

Fluorine-containing amino acids are becoming increasingly prominent in new drugs due to two general trends in the modern pharmaceutical industry. Firstly, the growing acceptance of peptides and modified peptides as drugs; and secondly, fluorine editing has become a prevalent protocol in drug-candidate optimization. Accordingly, fluorine-containing amino acids represent one of the more promising and rapidly developing areas of research in organic, bio-organic and medicinal chemistry. The goal of this Review article is to highlight the current state-of-the-art in this area by profiling 42 selected compounds that combine fluorine and amino acid structural elements. The compounds under discussion represent pharmaceutical drugs currently on the market, or in clinical trials as well as examples of drug-candidates that although withdrawn from development had a significant impact on the progress of medicinal chemistry and/or provided a deeper understanding of the nature and mechanism of biological action. For each compound, we present features of biological activity, a brief history of the design principles and the development of the synthetic approach, focusing on the source of tailor-made amino acid structures and fluorination methods. General aspects of the medicinal chemistry of fluorine-containing amino acids and synthetic methodology are briefly discussed.