Chemistry and Pharmacology of Fluorinated Drugs Approved by the FDA (2016–2022)

Abstract

Fluorine is characterized by high electronegativity and small atomic size, which provide this molecule with the unique property of augmenting the potency, selectivity, metabolic stability, and pharmacokinetics of drugs. Fluorine (F) substitution has been extensively explored in drug research as a means of improving biological activity and enhancing chemical or metabolic stability. Selective F substitution onto a therapeutic or diagnostic drug candidate can enhance several pharmacokinetic and physicochemical properties such as metabolic stability and membrane permeation. The increased binding ability of fluorinated drug target proteins has also been reported in some cases. An emerging line of research on F substitution has been addressed by using 18F as a radiolabel tracer atom in the extremely sensitive methodology of positron emission tomography (PET) imaging. This review aims to report on the fluorinated drugs approved by the US Food and Drug Administration (FDA) from 2016 to 2022. It cites selected examples from a variety of therapeutic and diagnostic drugs. FDA-approved drugs in this period have a variety of heterocyclic cores, including pyrrole, pyrazole, imidazole, triazole, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, triazine, purine, indole, benzimidazole, isoquinoline, and quinoline appended with either F-18 or F-19. Some fluorinated oligonucleotides were also authorized by the FDA between 2019 and 2022.

Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants

“…However, its chiral center at the 3′ position is prone to racemization during synthesis, separation, and storage, resulting in unstable optical purity. Over the past two decades, fluorine substitution has emerged as one of the indispensable structural features in contemporary pharmaceuticals. − Around half of the most commercially successful drugs (blockbuster drugs) now incorporate fluorine atoms within their structures . The metabolic stability of compounds can be enhanced through the protection of metabolism-prone sites, including those susceptible to racemization and oxidative metabolism, via isosteric substitution of fluorine and hydrogen atoms .…”

Design, Synthesis, and Biological Evaluation of Newly Synthesized Cinnamide-Fluorinated Containing Compounds as Bioactive Anticancer Agents

“…31 In addition, it has been reported that compounds containing a fluoro substituent were highly active anticancer agents against different cancer cell lines. 32 Several studies reported phenyl moiety with a 4-fluoro substituent as a key part of several potent EGFR-TK inhibitors with pronounced cytotoxic activity on several cancer cell lines. 33−35 Continuing our investigations on the preparation of newer bioactive compounds with active biological properties on human cancerous cell lines, 36−40 we have synthesized cinnamide-fluorinated compounds 2a−7 in 60−76% yield (Figure 1).…”

“…The high electronegativity of the fluorine atom in the aromatic part of these drug molecules plays an important role in changing the physicochemical properties and, hence, enhancing the biological potencies . In addition, it has been reported that compounds containing a fluoro substituent were highly active anticancer agents against different cancer cell lines . Several studies reported phenyl moiety with a 4-fluoro substituent as a key part of several potent EGFR-TK inhibitors with pronounced cytotoxic activity on several cancer cell lines. − …”

“… 31 In addition, it has been reported that compounds containing a fluoro substituent were highly active anticancer agents against different cancer cell lines. 32 Several studies reported phenyl moiety with a 4-fluoro substituent as a key part of several potent EGFR-TK inhibitors with pronounced cytotoxic activity on several cancer cell lines. 33 − 35 …”

Mild Pd-Catalyzed Decarboxylative Cross-Coupling of Zinc(II) Polyfluorobenzoates with Aryl Bromides and Nonaflates: Access to Polyfluorinated Biaryls

“…Owing to the unique physical and chemical properties, fluorinated compounds have attracted significant interest and attention from scientists across various scientific disciplines. Among them, polyfluorobiaryl motifs are ubiquitous building blocks in medicinal chemistry, functional materials, and ligand (Scheme a). Transition-metal-catalyzed cross-coupling reaction is undoubtedly one of the most prominent methods to construct polyfluorinated biaryls.…”