Highlights on U.S. FDA-approved fluorinated drugs over the past five years (2018-2022).

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutation in the cystic fibrosis trans-membrane conductance regulator (CFTR) gene [ 103 , 104 ]. It is most commonly found at least 1 out 3500 births in Caucasia population [ 105 ], 1 out of 3000 births in north Europeans, and 1 out of 30000 in Asian Americans [ 106 ]. Immune thrombocytopenia (ITP) is a kind of platelet disorder that is caused due to the destruction of platelets by immune system. Low platelet counts lead to easy bleeding and bruising. Endometriosis is a chronic with most common symptoms, such as infertility and pelvic pain [ 107 , 108 ]. It is a gynecological disorder occurring in around 10% of women of reproductive age [ 109 ]. The prime cause of this debilitating disease is the presence of endometrial tissues outside the uterus where the implanted cells secrete multiple cytokines and prostaglandin E2 that obtain an inflammatory response [ 107 , 108 ]. Rheumatoid arthritis (RA) is a chronic disease affecting joints as well as extra-articular or organs, including kidney, eye, digestive system, heart, lung, skin, and nerve system [ 110 , 111 ]. Antineutrophil cytoplasm antibody-associated vasculitides are small-vessel vasculitides that include eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, and microscopic polyangiitis [ 112 – 114 ]. In addition to drugs to combat cancers, infectious diseases, and CNS disorders, the CDER of U.S. FDA approved six drugs 53–58 having fluorine for the treatment of some other diseases as described above ( Fig. 6 ; Table 4 ). Symdeko 53 and Trikafta 57 were approved to treat cystic fibrosis (CF). Symdeko 53 is a combination of Tezacaftor and Ivacaftor, which functions as a CFTR corrector and a CFTR potentiator [ 115 ]. Trikafta 57 has three active ingredients, such as Tezacaftor, Ivacaftor and Elexacaftor that acts as CCFTR corrector, CFTR potentiator, and CFTR corrector [ 116 ]. As a SYK inhibitor, Tavalisse 54 was approved to treat chronic immune thrombocytopenia. Orilissa 55 is a drug for moderate to severe pain associated with endometriosis, which acts as a GnRH receptor antagonist [ 117 ]. To treat adults with moderately to severely active rheumatoid arthritis, Rinvoq 56 was approved as a JAK inhibitor. Tavneos 58 is a C5a receptor antagonist utilized to treat severe active antineutrophil cytoplasmic autoantibody–associated vasculitis [ 118 ]. The critical role of fluorine atoms and/or CF 3 group in drugs 53–58 ( Fig. 6 ) can also be manifested as discussed earlier from the structure-activity/property relationship perspective.

The prevalence of fluorine or groups of fluorine atoms or its isotope in the FDA-approved drugs manifests its significant role in the pharmaceutical research in terms of diagnosis and therapeutics. Judicious deployment of fluorine or groups of fluorine atoms in a molecule under investigation may lead to enhanced pharmacological and pharmacokinetic profiles with improved potency, decrease in pKa, higher permeability, decrease in clearance, and conformational constraint [ 31 – 34 ]. Inspired by the outstanding performance, sustainability, and a high pace of approval of fluorinated drugs in the past decade, pharmaceutical companies continued to explore fluorine-containing entities in an expectation to discover new medications to combat deadly diseases. It is noteworthy that FDA granted approval to four fluorine-containing drugs 59–62 within merely three months of 2023 ( Fig. 7 ). FDA approved Rykindo 59 and Jaypirca 60 for the treatment of schizophrenia and mantle cell lymphoma, respectively. Subsequently, Skyclarys 61 received approval for the therapy of Friedrich’s Ataxia. In addition, FDA granted approval to Joenja 62 for the treatment of activated phosphoinositide 3-kinase delta syndrome. The approval of these four drugs within such a short period of this year warrants that fluorine or group of fluorine atoms play a pivotal role in the pharmaceutical industry, indicating a great potential in the future trends of drug discovery and development. During the literature survey, excitingly we came across a number of fluorinated investigational new drugs (INDs) under different phases of clinical trials for the treatment of various human diseases [ 125 ]. Some of these INDs with their name (application number), indication, drug mechanism, and phases have been described. There are several fluorinated INDs under clinical trials for the treatment of various types of cancers that are discussed along one by one. BAY 2965501 ( NCT05614102 ) is the first-in-class diacylglycerol kinase zeta inhibitor (DGKzi), which is being evaluated in phase I for the treatment of advanced solid tumor. BI 907828 ( NCT05372367 ) is another MDM2 inhibitor in phase I studies to treat solid tumor [ 119 ]. MRTX1133 ( NCT05737706 ) is a potent, selective, and non-covalent KRAS inhibitor [ 120 ]. It is in phase I/II evaluation for solid tumor (advanced solid tumor, non-small cell lung cancer, colorectal cancer, and pancreatic adenocarcinoma). CFT1946 ( NCT05668585 ) is under phase I/II study to characterize the safety, tolerability, and preliminary efficacy as monotherapy and in combination with trametinib in patients with BRAF V600 mutant solid tumors. MRTX 1719 ( NCT05245500 ) is in phase I/II evaluation in solid tumors with MTAP deletion. GB 1211 ( NCT05240131 ) is a galectin-3 inhibitor being tested in phase I for the treatment of non-small cell lung cancer. AZD9833 ( NCT04818632 ) is under investigation in phase I for the treatment of breast cancer. Additionally, BLU-945 ( NCT04862780 ) is another IND in the phase I/II, in the patients with EGFR mutant non-small cell lung cancer. Ziftomenib ( NCT04067336 ) is an inhibitor of menin-MLL(KMT2A), which is in phase I/II clinical studies to treat patients with relapsed or refractory acute myeloid leukemia. Mezigdomide ( NCT03989414 ) in under investigation in the phase I/II clinical trial in participants with relapsed or refractory multiple myeloma and newly diagnosed multiple myeloma. AZD4573 ( NCT05140382 ) is in phase II for multicenter study to assess AZD4573 efficacy and safety as monotherapy or in combination with anti-cancer agents in patients with relapsed/refractory peripheral t-cell lymphoma or classical hodgkin lymphoma. Nirogacestat ( NCT05348356 ) is in phase II clinical trial to learn its effectiveness in ovarian granulosa cell tumors (OvGCTs). Nirogacestat is a γ-secretase inhibitor (GSI), which is hypothesized to decrease the growth and activity of ovarian granulosa tumors. Inavolisib ( NCT05306041 ) is a PI3K Inhibitor, which is under evaluation in phase II for the treatment of HER2-positive breast cancer [ 121 ]. Paltusotine ( NCT05361668 ) is in phase II to evaluate the safety, PK, and dose response in subjects with carcinoid syndrome. Emraclidine (CVL-231) ( NCT05443724 ) is a selective M4 receptor PAM, which is currently in phase II clinical trial to evaluate safety and tolerability in adult patients with Schizophrenia [ 122 ]. In addition, as a novel GlyT1 inhibitor, BI 425809 ( NCT05211947 ) is under phase III studies to evaluate the long-term safety in the patients with Schizophrenia [ 123 ]. MK-0616 ( NCT05070390 ) is a macrocyclic peptide that binds to PCSK9 and inhibits the interaction of PCSK9 with LDL receptors. It is in phase I being tested in participants with moderate renal impairment. Zunsemetinib ( NCT05511519 ) is an investigational oral mitogen-activated protein kinase-activated protein kinase 2 (MK2) inhibitor. Currently, it is in phase II study to investigate the efficacy, safety, tolerability, and PK/PD of ATI-450 versus placebo in patients with moderate to severe psoriatic arthritis. Asundexian ( NCT05686070 ) is an FXIa Inhibitor [ 124 ]. It is under investigation in phase III to learn more about asundexian for prevention of ischemic stroke in male and female patients aged 18 years and older who already had such a stroke due to a blood clot that formed outside the heart and travelled to the brain. In the view of above, we anticipate that some of these fluorine containing INDs in different phases of clinical trials will reach to FDA-approval for clinic use. Collectively, we believe that this concise review may further attract the attention of the drug discovery and medicinal chemistry community in both industrial and academic settings towards the intelligent application of fluorine and fluorine-containing groups in rational drug design to bring more and better medications to the clinic to improve the health and enhance the life expectancy of human beings.

This review has highlighted fluorinated drugs approved by the CDER of U.S. FDA over the past five years (2018–2022). It is noteworthy that 58 out of 247 representing nearly a quarter of the total are fluorine-containing drugs. Each of these drugs has been summarized and briefly discussed based on their therapeutic application areas, such as cancers, infectious diseases, CNS disorders and some other diseases. Despite the great challenge in finding the anticancer drugs given that each kind of cancer requires different specific diagnosis and target-based treatment strategies, FDA approved thirty fluorinated drugs 1–30 to diagnose, mitigate and treat various types of cancers including prostate, melanoma, acute myeloid, philadelphia chromosome–positive chronic myeloid leukemia, lung, breast cancer and so on in the last five years. Among them, Cerianna 19 and Pylarify 26 were approved as diagnostic imaging agents for their use in positron emission tomography to detect breast and prostate cancer, respectively. Twelve fluorine-containing drugs 31–42 received approval to treat a big array of infectious diseases including HIV, nausea, smallpox, influenza and many more. CNS research is one of the most challenging in the drug discovery and development due to highly sophisticated protection system of brain. Nevertheless, in the past five years, FDA approved ten fluorinated drugs 43–52 as novel therapeutic agents for CNS disorders, such as schizophrenia, insomnia, migraines, and Parkinson’s disease. In addition, Fluorodopa F-18 44 and Tauvid 50 were approved for the diagnosis of Parkinson’s disease and Alzheimer’s disease. Last but not least, FDA approved six fluorinated drugs 53–58 for other diseases, such as cystic fibrosis, chronic immune thrombocytopenia, endometriosis, rheumatoid arthritis, and severe active antineutrophil cytoplasmic autoantibody–associated vasculitis. In summary, the unique and successful applications of the fluorine and/or fluorine-containing groups may inspire the drug discovery and medicinal chemistry community in both industrial and academic settings to explore the fluorinated molecules in the early rational drug design process.

Fludrocortisone [ 1 , 2 ] as the first fluorine-containing drug was introduced to the market for commercial use in 1954 ( Fig. 1 ). Shortly thereafter, 5-fluorouracil [ 3 , 4 ] was another fluorinated drug brought to the clinic for the treatment of cancer in 1957 ( Fig. 1 ). Introduction of these two drugs drew the attention of pharmaceutical industry toward the biological applications of fluorine in drug discovery and development. In 1972, Ili Lilly and Company discovered a blockbuster antidepressant drug Prozac (Fluoxetine) and marketed it for medical use in 1986 ( Fig. 1 ). Extensive literature survey has revealed that more than 50% blockbuster drugs are the molecules having fluorine atom(s) or trifluoromethyl group [ 5 ]. Notably, among these medicines, Lipitor is considered the most profitable one ever launched to the market [ 6 ]. Over the past two decades, fluorine chemistry has demonstrated its potential applications in diverse domains, such as food, health, and energy industries. In addition, fluorine-containing compounds have been exploited for the advancement of technologies due to their unique electronic, physicochemical, and biological properties [ 7 – 12 ]. One of the exciting contributions of fluorine in the innovation of technology is the use of its isotope 18 F containing molecules in positron emission tomography (PET) in potential diagnosis, drug discovery and development [ 13 – 22 ]. It is well known that fluorine is extensively utilized in magnetic resonance imaging (MRI) as a diagnostic tool for early monitoring the different illnesses [ 23 – 26 ]. Furthermore, fluorine has shown its potential applications in peptide/protein engineering [ 27 – 30 ]. In fact, most important application of fluorine lies in the drug design to discover new entities. Judicious installation of fluorine or groups of fluorine atoms (e.g., CF 3 , CHF 2 , OCF 3 ) in a drug candidate may lead to improved pharmacological and pharmacokinetic profiles with increased potency, decrease in pKa, higher permeability, decrease in clearance, and conformational constraint [ 31 – 34 ]. The prevalence of fluorine in pharmaceuticals attracts the attention of synthetic community and encourages developing new synthetic methodologies to access structurally diverse fluorinated molecules. Consequently, numerous novel methods for the synthesis of unique fluorinated compounds have been reported in literature [ 35 – 45 ] in past few years. Recently, some review articles nicely covered FDA-approved fluorinated drugs year-wise until 2021 [ 46 – 50 ]. However, no update is available on FDA-approved fluorinated drugs in 2022. Moreover, there is no report available in the literature that presents a concise information about fluorinated drugs approved by FDA based on their therapeutic areas in a single document in the past five years (2018–2022). Therefore, there is a need of a concise and informative summary on fluorine-containing therapies to provide the latest update for the drug discovery and medicinal chemistry research community. The bar graph displays the total numbers of FDA-approved drugs along with fluorinated drugs spanning from 2018 to 2022 ( Fig. 2A ). The Center for Drug Evaluation and Research (CDER) of the U.S. FDA approved a total of 247 drugs including small and macromolecules from 2018 to 2022. Fifty-eight out of them are fluorinated small molecules for various therapeutic purposes, such as cancers, infections, CNS disorders and some other diseases ( Fig. 2B ). This review presents an overview with highlights on the fluorinated drugs for diagnosis, mitigation, and the treatment of various types of cancers, infectious diseases, CNS disorders and some other diseases. It also provides the details about these approved fluorinated drugs, such as trade name, approval date, active ingredients, company developers, indications, and drug mechanisms.