The FDA’s Center for Drug Evaluation and Research (CDER) approved 55 new molecular entities (NMEs) and new therapeutic biological products in 2023, including 33 small molecule drugs. Of these 33 small molecule drugs, 11 contain at least one fluorine atom. In other words, one-fifth of the new drugs approved by CDER this year are fluorinated drugs.
Why is fluorine important to those Drugs
The advantages of fluorinated drugs are mainly due to the presence of fluorine atoms in their molecular structure, which imparts the drugs some special properties and thus gives them some advantages in treatment. Here are some of the advantages of fluorinated drugs:
- Enhanced biological activity
The introduction of fluorine atoms can usually enhance the biological activity of molecules, making the drugs more potent. This is because fluorine has a greater electron affinity, and its influence on the molecular structure can lead to stronger interactions, enhancing the binding ability of the drug to the target.
- Improved metabolic stability
Fluorinated compounds are generally more resistant to metabolic enzymes, which can increase the metabolic stability of drugs, prolong their half-life in the body, and thus reduce the frequency of administration.
- Improved drug absorption
The introduction of fluorine atoms helps to improve the solubility of drugs, thereby improving their oral absorption. This is important for the development of oral drug treatment plans.
- Improved drug distribution properties
The presence of fluorine atoms can change the distribution properties of drugs, making them better able to cross tissue barriers, such as the blood-brain barrier, and increase the concentration of drugs in target tissues.
- Reduced side effects
Due to the structural characteristics of fluorinated compounds, it is sometimes possible to reduce the effects of drugs on non-target tissues through precise design, thereby reducing the occurrence of adverse reactions.
Overall, the design and application of fluorinated drugs can increase the therapeutic effect of drugs while reducing adverse reactions, thereby increasing the safety and efficacy of drug treatment. However, it should be noted that fluorinated drugs may also bring some special challenges and safety issues, so it is necessary to comprehensively consider various factors in drug research and application.
Below are brief review of the 11 Fluorinated Drugs Approved by the FDA in 2023.
- Pirtobrutinib
Pirtobrutinib is a small molecule drug that is a highly selective non-covalent inhibitor of Bruton’s tyrosine kinase (BTK). Its high selectivity brings benefits, including a lower rate of discontinuation due to adverse events and a lower incidence of atrial fibrillation. Unlike covalent BTK inhibitors (such as ibrutinib, which bind to Cys481 in the BTK active site), pirtobrutinib’s inhibitory activity can be maintained even if BTK’s Cys481 mutates. Cys481 mutation appears to be the most common cause of resistance to covalent BTK inhibitors. Innovative reversible BTK inhibitors such as pirtobrutinib are characterized by reduced off-target side effects and avoidance of the development of drug resistance. These types of reversible BTK inhibitors are of interest not only for the treatment of B-cell malignancies, but also for the treatment of many autoimmune diseases.
In January 2023, the FDA approved pirtobrutinib through the accelerated approval pathway for the treatment of relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy.
The 1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole group is a key structural element in the pirtobrutinib molecule. The number of drugs containing the 1H-pyrazole structure has increased significantly, and the best-selling drugs of this type include ibrutinib, ruxolitinib, axitinib, niraparib and baricitinib.
2. Omaveloxolone
Omaveloxolone is a semisynthetic triterpenoid compound with antioxidant and anti-inflammatory properties. Omaveloxolone acts as an activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor that mitigates oxidative stress. In patients with Friedreich’s ataxia (a genetic disease involving mitochondrial dysfunction), the Nrf2 pathway is impaired, and Nrf2 activity is lower. Omaveloxolone was approved by the FDA in February 2023 for the treatment of Friedreich’s ataxia in adults and adolescents 16 years of age and older. In addition to activating Nrf2, omaveloxolone also inhibits the NF-κB signaling pathway, promoting antioxidant, anti-inflammatory, and anti-apoptotic mechanisms。
3 Leniolisib (Joenja)
Leniolisib is a selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor. The FDA approved leniolisib on March 24, 2023, making it the first drug to treat activated phosphoinositide 3-kinase delta syndrome (APDS). APDS is a primary immunodeficiency caused by mutations in genes encoding PI3Kδ, which increases PI3Kδ activity, leading to immune dysfunction and increased susceptibility to infection. Leniolisib can inhibit overactive PI3Kδ. Studies on the use of leniolisib to treat primary Sjögren’s syndrome are ongoing.
The leniolisib molecule contains a fluorinated structure with a 2-methoxy-3-(trifluoromethyl)pyridine.
- Fezolinetant (Veozah)
Fezolinetant is a non-hormonal drug for the treatment of moderate to severe vasomotor symptoms (NK3 receptor antagonist) caused by menopause, which plays a role in the hypothalamus-pituitary-gonadal (HPG) axis. . Older generations of NK3 receptor antagonists, such as osanetant and talnetant, but only fezolinetant targets the HPG axis, which may be due to the favorable pharmacokinetic properties of fezolinetant that can cross the blood-brain barrier. Fezolinetant was approved by the FDA in May 2023 and marketed as VEOZAH.
The fezolinetant molecule contains a fluorinated structure of 4-fluorobenzoyl.
5. Perfluorohexyloctane
Perfluorohexyloctane is a semi-fluorinated alkane with 6 perfluorinated carbon atoms and 8 hydrogenated carbon atoms. It is an inert, slightly amphiphilic compound. Because it is a completely non-aqueous liquid, microbial growth is not possible. Therefore, its drugs do not need to be mixed with any preservatives. Perfluorohexyloctane has been used as a vitreous substitute in the field of ophthalmology. It was approved by the FDA on May 18, 2023 for the treatment of dry eye disease.
Perfluorohexyloctane is administered ophthalmically to alleviate symptoms of dry eye disease, increase tear film breakup time, and increase lipid layer thickness. Perfluorohexyloctane has low surface and interface tension and can spread rapidly on the ocular surface. Due to its refractive index being similar to that of water, it has minimal visual disturbances. Perfluorohexyloctane interacts with the air-liquid interface of the tear film and forms a monolayer to prevent tear evaporation.
6. Lotilaner (Xdemvy)
Lotilaner is an ectoparasiticide that belongs to the isoxazoline family of compounds. Lotilaner is primarily used for veterinary purposes as an antiparasitic agent to treat flea and tick infestations in animals. Lotilaner is a non-competitive antagonist of the γ-aminobutyric acid (GABA)-gated chloride channel (GABACl) that is selective for mites. Inhibition of GABACl causes a paralytic action in the target organism, leading to death. On July 25, 2023, lotilaner was approved by the FDA for the treatment of demodicosis blepharitis, becoming the first and only drug approved to treat demodicosis blepharitis. The lotilaner molecule contains two fluorinated structures with three trifluoromethyl groups.
7. Motixafortide (Aphexda)
Motixafortide (Aphexda) is a cyclic peptide hematopoietic stem cell mobilizer used to improve stem cell collection prior to autologous transplantation. Hematopoietic stem cell transplantation (HSCT) is commonly used for blood cancers: high-dose chemotherapy destroys cancerous blood cells, which are then replaced by the infusion of the patient’s own stem cells (i.e., autologous transplantation).
Motixafortide’s mechanism is similar to that of the previously approved Plerixafor, it is an inhibitor of C-X-C motif chemokine receptor 4 (CXCR4), a protein that anchors stem cells to the bone marrow matrix. Motixafortide was approved by the FDA in September 2023 for use in combination with filgrastim for stem cell mobilization prior to autologous stem cell transplantation in patients with multiple myeloma. It is also being studied in combination with pembrolizumab for the treatment of pancreatic cancer.
The motixafortide molecule contains a fluorinated structure, an N-4-fluorobenzoyl arginine.
8. Etrasimod (Velsipity)
Etrasimod is a new generation of selective sphingosine-1-phosphate (S1P) receptor modulators that target S1P1, 4, and 5. S1P receptors are membrane-bound lysophospholipid signaling molecules involved in the sequestration of circulating peripheral lymphocytes in lymph nodes. S1P receptor modulators can play a role in the treatment of immune diseases, such as ulcerative colitis. Etrasimod was approved by the FDA on October 13, 2023, for the treatment of moderate to severe active ulcerative colitis in adults. The etrasimod molecule contains a trifluoromethylphenyl fluorinated structure.)
9. Repotrectinib (Augtyro)
Repotrectinib (Augtyro) is a next-generation tyrosine kinase inhibitor (TKI) that targets resistance in the treatment of non-small cell lung cancer (NSCLC), specifically resistance caused by ROS1 gene mutations. ROS1 mutations are one of the oncogenic drivers in NSCLC. Repotrectinib has a compact macrocyclic structure that limits unfavorable interactions with resistance mutation hotspots. While resistance to multiple TKIs, including crizotinib, lorlatinib, taletrectinib, and entrectinib, has been reported, no cases of resistance to repotrectinib have been reported yet.
On November 15, 2023, the FDA approved repotrectinib for the treatment of locally advanced or metastatic ROS1-positive NSCLC.)
10. Nirogacestat (Ogsiveo)
Nirogacestat is a small molecule gamma-secretase inhibitor that is a potential therapeutic agent for desmoid tumors. Desmoid tumors are characterized by the abnormal activation of Notch signaling. Inhibition of gamma-secretase can inhibit Notch signaling, thereby阻碍ing the growth of desmoid tumors.
Nirogacestat was approved by the FDA on November 27, 2023 for adult patients with progressive desmoid tumors who require systemic therapy. The Nirogacestat molecule contains a fluorinated structure of 6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-amine.
11. Paxlovid
Paxlovid (nirmatrelvir, ritonavir) is a medication for people with mild to moderate Covid-19. It contains two active ingredients, nirmatrelvir and ritonavir.
Nirmatrelvir is an oral protease inhibitor with oral bioavailability that inhibits 3C-like protease (3CLPRO), targeting its key cysteine residue. The inhibition of 3CLPRO can effectively inhibit viral replication.
Nirmatrelvir contains a fluorinated structure of an N-trifluoroacetyl-3-methylvaline.
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