Improvement of the structure of fluorinated drugs

The introduction of fluorine atoms or fluorine-containing groups into drug molecules can change the permeability and metabolic stability of drug molecules, regulate their PKA and liposolubility, and affect the absorption, distribution and interaction with biological targets of drug molecules, thus gradually becoming a common means of drug screening.

Of the 38 small molecule drugs approved by FDA in 2018, 18 are fluorine-containing drugs, such as biktarvy used to treat type 1 human immunodeficiency virus (HIV) infection and erlada (apalutamine) used to treat non metastatic castration resistance to prostate cancer.

Last year, NIBR summarized the possible metabolic pathways of fluorine-containing drugs with different structures in human body in ACS Medical Chemistry Letters, some drug molecules will decompose to produce fluoride and fluorine-containing toxic metabolites, and put forward feasible suggestions on some structural improvements.

For example: Monofluoroalkanes

When there are nucleophilic sites in the molecule, monofluoroalkyl is easy to participate in SN2 nucleophilic substitution reaction and C-F bond breaks. It can gradually decompose 60% - 90% in the range of 50 ℃ and human blood pH, and release fluoride anion. In contrast, the decomposition of non fluorine parent was less than 2% under the same conditions. The carboxylic acid anion in 4-fluoleucine (5) can attack the fluorine substituted tertiary carbon site and break the C-F bond. The driving force of defluorination decomposition of these compounds is that the formation of penta cyclolactone is more stable in thermodynamics. If a carbon element is added between carboxylic anion and fluorine atom, the defluorination tendency will be greatly reduced. In addition to the effect of intramolecular nucleophilic sites, monofluorination of active sites (such as benzyl, allylic, carbonyl α) can also interact with nucleophiles in vivo, such as drug molecule 6 can react with glutathione in rat brain homogenate, with a half-life of only 20 minutes.