Rattibha

Increased use of Fluorine in pharmaceuticals - an emerging trend.
Keeping reading the thread to know some interesting details.

Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals.
About half of the most successful drugs (blockbuster drugs) contain fluorine atoms.

Rise of biologics is a real thing and focus of therapeutics is slowly shifting from small molecules to biologics.

But interestingly that doesn't seems to affect flouro-pharmaceuticals. 20% of total marketed drugs have been fluoro-pharmaceuticals in the past.
In the last 6 years 35% of approved small molecules have been fluoro-pharmaceuticals. One in every 3 new API's contains fluorine.

191 out of 839 (22%) small molecule drugs approved over the time period 1991-2019 were Fluoro-pharmaceuticals. Overall there were 354 fluorinated drugs on 2020.

Percentage of Fluoro-pharmaceuticals among total registered synthetic drugs
2015 : 34%
2016 : 23%
2017 : 25%
2018 : 51%
2019 : 43%
2020: 35%

Approximately 25% (14 out of 53) of all drugs approved in 2020 by the FDA contain Fluorine. This percentage increases by more than a third (14 out of 40) if only NCEs are taken into consideration. These figures highlight the clear impact of fluorine in drug discovery.

What's the reason for this high prevalence of Fluorine in pharmaceuticals?
Fluorine is often added to drug structure during design, as even a single atom can greatly change the chemical properties of the molecule in desirable ways.

Introduction of fluorine atoms into organic compound molecules can give these compounds new functions and make them have better performance. Therefore, the synthesis of fluorides has attracted more and more attention from biologists and chemists.

Reasons
1. Fluorine is second smallest atom after hydrogen. So, H can be easily replaced with F & doesn't affect parent structure much.
F can modify bioisosteric effects on properties such as binding affinity and H-bonding
interactions, where fluorine replaces a -H or -OH.

F acts as a weak hydrogen bond acceptor and
can be used as a bioisostere of the hydroxyl group (OH)

2. C-F bond is stronger. Increases stability of the drug.
This delays the drug metabolism & hence increases the half life of the drug.
Which warrants less frequent dosing.

3. F is the most electronegative atom in periodic table.
As C-F bond is stronger & has extremely low polarisation, it becomes less ionic, less water soluble & more fat soluble(more lipophilic).

This increases cellular penetration as fat soluble drugs can easily pass through the phospholipid bilayer of cellular membrane.
This tremendously increases drug absorption and bioavailability.

4.Effects on acid/base (pKa) properties of neighboring functional groups,
for example, the lowering of amine function pKa induced by the presence
of fluorine atoms.

The combination of these
unique properties of Fluorine presumably exerts subtle effects on the
absorption, distribution, metabolism, and excretion (ADME) of drug candidates.

The incorporation of fluorine atoms or fluorinated groups into appropriate positions in pharmaceuticals has been established as a very good strategy in medicinal chemistry and several fluorinated drugs have been developed.

One notable example is difference in properties of natural glucocorticoid- Cortisol (hydrocortisone) & synthetic glucocorticoids Betamethasone and dexamethasone.

Synthetic ones are produced from hydrocortisone by just adding a Fluorine atom at 9th position (Dexamethasone) and additional -CH3 group at 16th position (Betamethasone)

Addition of fluorine atom has increased the half life of the drug, increased the therapeutic effect by 25-40 times, decreased the equivalent dose needed.

Several inhaled general anesthetic agents, including the most commonly used inhaled agents, also contain fluorine.
1st fluorinated anesthetic agent, halothane, proved to be much safer (neither explosive nor flammable) and longer-lasting than those previously used.

Modern fluorinated anesthetics are longer-lasting still and almost insoluble in blood, which accelerates the awakening.
Examples- sevoflurane, desflurane, enflurane, and isoflurane

Prior to the 1980s, dominant class of antidepressants were TCA (Tricyclic antidepressants) which had so many adverse effects. Because it inhibited reuptake of serotonin (desired effect) & norepinephrine (undesired effect)

The first drug to inhibit only the serotonin reuptake was Prozac (Fluoxetine) & was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice due to reduction in adverse effects

It gave birth to the extensive selective serotonin reuptake inhibitor (SSRI) antidepressant class and is the best-selling antidepressant.

Fluoxetine has a trifluoro-methyl group in its structure.
In particular, the trifluoromethyl group is a unique structural motif, which plays a crucial role in pharmaceuticals due to its profound effect on absorption, distribution, metabolism & excretion (ADME) of drug candidate.

An analysis of fluoropharmaceuticals revealed that pharmaceuticals with monofluorinated moieties
(67.2%) are most common,
followed by drugs with trifluoromethyl groups (19.2%) these
two categories comprise 86% of all fluoro-pharmaceuticals.

But in 2019 the number of CF3-containing drugs was
8, while that of the monofluorinated (C-F-)groups containing drugs was only 7.
These numbers are in
contrast to the past data of 19% & 67%, but may reflect the
increasing diversity of the trifluoromethylation reactions.

These
facts indicate that synthetic methodology is providing access to
new fluorinated motifs with unique physicochemical properties
that medicinal chemists will take advantage of.

The number of organofluorine compounds of a given
chemotype that is investigated as potential drug candidates
can be expected to depend strongly on the availability of
synthetic methods to access the relevant moieties.

The potential of fluoro-pharmaceuticals is expected to
increase in the future in parallel to advancements in fluoro-
functionalization methodologies.

In recent years, a vast number
of synthetic strategies have been reported for the synthesis of
SCF3,
OCF3 and even rare pentafluoro-λ6
-sulfanyl (SF5)-containing compounds, including SF5−pyridines.

Further
progress in the development of synthetic methods for the
formation of fluorinated heterocyclic compounds, including
asymmetric reactions, could help to increase fluorine-based drug
discovery in the future.