MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS

• Дата: 2025
• Автори: Han, Jianlin, Wzorek, Alicja, Ono, Taizo, Klika, Karel, Soloshonok, Vadim
• Формат: Стаття
• Мова: English
• Опубліковано: V.I.Vernadsky Institute of General and Inorganic Chemistry 2025
• Онлайн доступ: https://ucj.org.ua/index.php/journal/article/view/733
• Назва журналу: Ukrainian Chemistry Journal

This review profiles ten marketed pharmaceuticals approved by the US Food and Drug Agency within the last five years that feature aliphatic fluorination – a key structural feature pivotal to their biological activity. These include ivosidenib, developed for the treatment of acute myeloid leukemia and cholangiocarcinoma (bile duct cancer); ubrogepant, approved for the acute treatment of migraines; asciminib, prescribed for the treatment of chronic my­eloid leukemia in the chronic phase; omaveloxolone, used in the treatment of Friedreich’s ataxia, a rare genetic disorder causing progressive damage to the spinal cord, peripheral nerves, and brain; flurpiridaz (18F), a radioactive diagnostic agent for myocardial perfusion imaging by positron emission tomography; upadacitinib, designed to address several inflammatory and autoimmune conditions, including rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondyloarthritis; tezacaftor, approved for the treatment of cystic fibrosis as an effective remedy; alpelisib, prescribed for the treatment of breast cancer, effectively inhibiting tumor growth and abnormal cell proliferation; pretomanid, used in combination therapies for the treatment of extensively drug-resistant and multi-drug-resistant tuberculosis; and atogepant, approved for the preventive treatment of migraines in adults, targeting both episodic and chronic  migraines. Molecules featuring aliphatic fluorination present challenges due to higher production costs and the complexity of predicting their biological profiles. However, the undeniable medicinal benefits of aliphatic fluorination invigorate this area of research, paving the way for the development of more innovative drugs to enter the pharmaceutical market. Beyond the incorporation of aliphatic fluorine atoms, six of the pharmaceuticals discussed in this review feature residues of amino acids or their derivatives as pivotal structural design ele­ments. Another characteristic shared by all these drugs is their chirality, with each molecule possessing between one and six stereogenic carbons. Special attention should be directed toward the phenomenon of self-disproportionation of enantiomers (SDE), a behavior observed in enantiomerically enriched compounds. The SDE properties of chiral drugs, particularly those containing fluorine and/or amino acid residues, represent a vital public safety concern, necessitating rigorous evaluation of enantiomeric purity. Additionally, caution should be exer­cised in light of growing public concerns over the potential harmful effects of fluorine on human health. Since fluoride is recognized as the final metabolite of organic fluorinated compounds, patients prescribed fluorine-containing drugs should consult their physicians about non-fluorinated alternatives where available or take steps to limit fluoride exposure from other sources, such as fluoridated water and industrially produced foods treated with fluorinated agrochemicals. Despite these concerns, it remains an undeniable fact that fluorine-containing drugs are indispensable in modern medicine. They provide life-saving treatments, improve quality of life, and drive medical innovation addressing urgent health challenges and laying the foundation for future advancements in healthcare.