“It is fairly common for drugs to be classified as weak acids or bases or perhaps more accurately as acids, bases, neutral, or zwitterionic.” Often the acidic or basic group is key part of the pharmacophore, and as such tend not be optimised by fine tuning the pKa. This very useful review is a comprehensive study of the effect acidic and basic compounds. Table 1 to 4 should be printed out by any compound designing chemists, and carried around as a reference. These summaries the effect on ADMET properties of ionised molecules from several dozen papers. The selected plot above (Figure 5) showing the clear effect of having ionisable group on aqueous solubility. However, having read the rest of the paper you will be left with the view that having a neutral compound as a drug is the best outcome, given that both lipophiliic acids and bases tend to have some kind of ADMET issue.
Acidic and Basic Drugs in Medicinal Chemistry: A Perspective J. Med. Chem. 2014, 57, 23, 9701–9717
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