Applications of Fluorine atom in Drug discovery

Some years ago, there was good review in drug discovery about the applications of fluorine. The perspective was published by researchers in BMS. There were many informations about fluorine based on their experience and published data. I think this is still useful for Med Chem.
It was published in 2015 from ACS.
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00258

And recently same author who is researcher in BMS reported new review about the review!
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b01788
I skimmed the review today (59 page! Too long for me ;-)). There are some examples that were reported in previous review but there are lots of new insights and examples of fluorine. The article mainly focused on
Bioisosteric replacement of molecules with fluorine. Bioisosteric replacement is often used in drug discovery to not only maintain potency but also improve metabolic stability, solubility or any parameters.
For example, the author describes about replacement from tert-butyl group to tri-fluoro cyclopropane analogue in “Table3”. It was interesting for me because it is not simple replacement, from tert-Bu to try-fluoro-dimethly group. Also there are some same replacement examples in different protein targets.

Strategy of metabolic block with fluorine atoms is some time easy to understand and medicinal chemists try to introduce fluorine atoms in their compounds. But application of fluorine is not limited in the strategy. An interesting examples are described in the article.
Introduction Fluorine atom in aromatic ring in Compound 174 can improve solubility of the compound from 15mg/mL to >500 mg/ml. The effect of the fluorine is not clear but the author describes the fluorine atom polarizing the adjacent N−H affects the solubility.

And I surprised because fluorine atom strategy is also effective for peptide drug discovery. In table 29, fluoro- derivatives of 36-residue peptide derived from amino terminus of human parathyroid hormone (hPTH) have binding potency for PTH receptor. If there are lots of cost effective fluorinated amino acids are available, can we design more potent peptide derivatives ?

New finding of fluorine effects creates new strategy for drug design. And sometime it is needed new chemistry to make fluorinated building blocks or conduct fluorination reactions.

Medicinal chemists need to catch up both new strategy for drug design and synthetic chemistry I think.