"Treasure Boy" - fluorine atoms.

Fluoroatom is considered to be a hydrogen atom, carbox, sulfonyl and cyanide potential bioelectronics due to its unique physical and chemical properties, and is often considered by the pharmaceutical community as a universal key.
review the history of the drug, and since the first fluorine replacement drug, fluorohydrocang, was approved for sale in 1955, the FDA-approved drug-containing drug has sprung up.
let's talk about how fluoroatoms are gaining popularity among drug chemists.

Figure 1. The number of fluorine-containing alternative drugs approved by the FDA by the end of 2019 is derived from the beginning of the 2020 FDA approval of fluorine-containing drugs from January-May 2020, but it does not prevent the FDA from reviewing the process.
The FDA has approved 22 drugs, four biopharmaceuticals and 18 small molecule compounds since January 2020.
of these compounds, nine of which carry F atoms, accounting for a relatively high proportion of 41% of approved drugs (Table 1).
structural analysis from 9 drugs, with the exception of Fluorostiol F18, the majority of proportion F has replaced the benzene ring position and has been replaced mainly by single F, such as Avaprotinib, Osilodrostat, etc.
from an indications perspective, 5 are oncology drugs, one is pain-related drugs, one is endocrine-related therapeutic drugs, two of which (Fluorostiol F18 and Flortaucipir F18) have special characteristics, are radiodiagnostic reagents with 18F isotopes.
mainly because of the positive electron emission performance and the short half-life (109.8min) nature of the 18F, which makes it a balm in PET imaging.
can be seen, F atoms in the structural design is widely used and tend to replace the aromatic ring, in the indications have a certain degree of accessibility and safety.
despite the passage of time, pharmaceutical chemists are still enthusiastic about the F-atom.
. From January to May 2020, the FDA approved fluorine-containing drug information
data sources: FDA official website 02 fluorine atoms in the drug structure 2.1 closed metabolic sites, improve metabolic stability F is a commonly used closed group in compound metabolic modification, due to its bond energy and reaction is lower than H atom, and compared with other closed groups, its molecular weight is small, less molecular size.
in drug design, it is usually introduced into small molecular compounds, to block the site of oxidation-prone metabolism, and thus improve the metabolic stability of the compound, prolong the drug's action time in the body.
commonly introduced in the aromatic ring to F, methyl hydrogen replaced with multiple F, preventing its metabolism in the body.

Figure 2. F replaces closed metabolic site lipid reduction drug by folding wheat cloth is optimized by closed metabolic site: the pilot compound 1 cyclamide replacement base optimization to obtain the compound SCH-48461.
in order to reduce the production of inactive metabolites and improve drug activity, according to the ANALYSIs of SCH-48461 metabolites, a series of metabolic-related compounds were designed and synthesized, and the final introduction of F, i.e. by folding wheat cloth, was introduced in the hydroxylization position and demethylation location of the benzene ring.

Figure 3. The development process of the yi-turned-wheat cloth needs to pay special attention to the F-atom is not what you want to introduce, and whether its introduction will lead to more harm than good results.
studies have shown that F produces the toxic metabolite fluoroacetic acid in certain molecules, which has lethal doses of 0.1-5 mg/kg, 0.05 mg/kg and 2-10 mg/kg in rats, dogs and humans, respectively.
researchers have summarized the structure of compounds that may produce fluoroacetic acid (see Figure 4), which requires special attention and avoidance if the following structures are produced during the metabolism of the compounds.
commonly used chemotherapy drug 5-fluorouretic in the body metabolism will produce fluoroacetaldehyde and fluoropropyl acid, and then produce fluoroacetic acid, and as 5-fluorourea precursor drug caperabin in the body will also produce fluoroacetic acid, which may be the clinical process of heart toxicity and neurotoxicity.

Figure 4. Known fluoroacetic acid metabolism precursors and 5-fluorouria metabolism pathways, derived from the reference s1, 2.2 to improve the affinity, improve bioavailability due to the F-atom's fat-fatproperty (s.14) better than the H-atom this advantage, the introduction of F-replacement helps to improve the compound's lipid affinity, promote membrane penetration, improve biological utilization.
take the sugar-lowering drug cestalitin as an example: in the course of the design of the statin drug, the early obtained more active but less biologically viable compound 2.
through in vitro osmosis and rat liver venous intubation studies show that due to low permeability of the compound, the compound 2 in the location of triazole to replace the ethyl to trifluoromethyl, improve the compound's lipid, so that the bioavailability increased about 20 times, further increase the number of benzene ring F replacement, and finally obtained the bioavailability of up to 76% of the DPP-IV inhibitor siratetine.

Figure 5. The research and development course of ceitalitin 2.3 adjusts pKa, reduces the experientirate pKa with the increase of F substitution, reduces the molecular alkaline reduction experientre rate, and notes that the central group within four or five keys of F will be affected.
a study of the development of BACE1 inhibitors associated with Alzheimer's disease showed that the introduction of CF3 groups to replace the pKa value of the molecule and reduce the P-gp experion rate, thereby reducing the loss of molecules when crossing the blood-brain barrier, and enhancing brain penetration.

Figure 6. BACE1 inhibitors can be seen in summary, F atoms in metabolism, osmotic absorption plays an important role.
besides, as the "treasure boy", F Atomics has many other functions.
such as reducing the production of active metabolites, avoiding inhibition of metabolic enzymes, as a hydrogen bond receptor and amino acids in the body to form hydrogen bonds, improve molecular effectiveness and so on.
but also to evaluate and analyze the advantages and disadvantages of introducing F-atoms, so as not to backfire.
References . . . Benjamin M. Johnson et al. Blain and Pharmaceutical Aspects of The Sioves. J. Med. Chem. 2019. The FDA's official website , Nicholas A. Meanwell . Rubio and The Design and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 14, 5822-5880. Steve Swallow. The Lyono in The Sabres. Progress in The Sauerd. 2015, 54, 65-133. Dooseop Kimet al. (2R) - 4-Oxo-4- (Trifluoromethyl) - 5, 6-dihydro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Orally Active Dipeptidyl Peptidase IV Dyer for Treatment 2 Diabetes. J. Med. Chem. 2005, 48, 141-151. Hans Hilpert et al. beta-Secretase (BACE1) With High In Vivo EE Ee for Clinical Evaluation in Alzheimer's Disease. J. Med. Chem. 2013, 56, 10, 3980-3995.