Aqueous solubility and blunt SAR

Chemistry control of aqueous solubility is poor because, except for a few very specific exceptions, chemistry SAR is blunt. In this respect, control of solubility like that of permeability is poor. Solubility due to excessive lipophilicity 

FIGURE 22.2 Minimum acceptable drug solubility as a function of projected clinical potency (O.l-lOmg/kg) and intestinal permeability Oow-avg-high K.  

Changing the p T of an acidic or basic group in a molecule so that more of the compound exists in the ionized form at physiological pH lowers log D (at about pH 7) and, in general, should improve aqueous solubility. The improvement in solubility is limited, however, if the solubility of the neutral form of the compound (the inherent solubility) is very low. The situation is worsened if the starting p Tg is far from 7. We find this to be a particular problem with weak bases. Weakly basic pyridines, quinolines, quinazo-lines and thiazoles seem to be frequent members of combinatorial libraries. Understanding the ionization behavior of drugs and how this property relates to oral absorption is extremely complex and likely beyond the capability (and interest) of many medicinal chemists. The reader is referred to an excellent recent review in this complex area.  

The extent of poor aqueous solubility may be experimentally underestimated in a combinatorial library. No 

---