"Treasure Boy" - fluorine atoms.

TextThefluorine atoms of hydrogen peroxide are considered to be the potential bioelectronics of hydrogen atoms, carinate, sulfonyl and cyanide due to their unique physical and chemical properties, and are often considered by the pharmaceutical community as the universal keyLooking back at the history of the drug, the FDA-approved drug containing drugs has sprung up since the first fluorine replacement drug, fluorohydrocangas, was approved for market in 1955Let's talk about how fluoroatoms are gaining popularity among drug chemistsThe beginning of 2020 is ups and downs, but it won't stop the FDA from reviewingSince January 2020, the FDA has approved 22 drugs, 4 biopharmaceuticals and 18 small molecule compoundsNine of these compounds carried 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 replaced in the benzene ring position and has been replaced mainly by single F, such as Avaprotinib, Osilodrostat, etcFrom an indications perspective, 5 are oncology drugs, one is pain drugs, one is endocrine-related therapeutic drugs, two of which (Fluorostediol F18 and Flortaucipir F18) are special, radiation diagnostic reagents with 18F isotopesThis is mainly due to the positive electron emission performance and the short half-life (109.8min) nature of the 18F, which makes it a balm in PET imagingcan be seen, F atom in structural design is widely used and tends to replace the aromatic ring, in the indications has a certain accessibility and safetyDespite the passage of time, pharmaceutical chemists are still enthusiastic about the F-atomForm 1Fda approves fluorine-containing drug informationfrom January to May 20202.1 Closed metabolic sites, improve metabolic stability
F is a commonly used closed group in compound metabolic transformation, thanks to its bond energy and reaction activity are lower than H atoms, and compared with other closed groups, its molecular weight is small, the molecular size of the less In drug design, F is usually introduced into small molecular compounds, which is used to block sites of oxidation-prone metabolism, thereby improving the metabolic stability of the compounds and prolonging the time of action of the drug in the body It is common to introduce F and methyl hydrogen on the aromatic ring to replace it with multiple Fs, preventing its metabolism in the body The lipid-lowering drug is optimized by closed metabolic sites: the lead compound 1 is optimized for 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 SCH-48461 metabolite analysis, a series of metabolic-related compounds were designed and synthesized, and finally the introduction of F, i.e by folding wheat cloth, was introduced in the hydroxylized bit and demethylation location of the benzene ring Pay special attention to the F-atom is not what you want to quote, and consider 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 fluoropropyrate, and then produce fluoroacetic acid, and as 5-fluoroureinto precursor drug caperabin in the body will also produce fluoroacetic acid, which may be the clinical process of heart toxicity and neurotoxicity 2.2 Improve the fat-fat, improve the bioavailability because the F-atom's fat-fat-like (s.14) is superior to the advantage of H-atom, the introduction of F to replace the compound's fat-fat, promote membrane penetration, improve bioavailability take the sugar-lowering drug cestalitin as an example: in the design of the nitalatin 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 caused by the compound 2 in the location of triazole replaced with the acetone in triazole to triple fluoromethyl, improve the fat-fat properties of the compound, so that the bioavailability increased by 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 sitalestine 2.3 Adjust pKa, reduce the experientiention rate
pKa with the increase of F substitution, reduce molecular alkaline reduction of the experientiby rate, need to pay attention to the distance from F four or five bonds within the central group 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 In summary, f atoms play an important role in metabolism and osmosis absorption In addition, as the "treasure boy", F Atom has many other functions Such as reducing the production of active metabolites, avoiding the 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 it is also necessary to evaluate and analyze the pros and cons of introducing F atoms so as not to be counterproductive .