The SERM's were all filtered out because their CLOGP value was greater than 5. It is important to realize that LogP is defined as the partition coefficient of the neutral molecule in octanol/water. However, the SERMS are not neutral at physiological pH: they all contain a tertiary nitrogen which becomes mostly positively charged by taking up a proton. Their lipophilicity is therefore NOT determined by the PARTITIONING of the NEUTRAL species in octanol/water, but by the DISTRIBUTION of both the neutral and positively charged forms of the molecule. The distribution coefficient is given by logD.

Introduction

Many drugs are weak acids or bases. This means that they contain at least one site that can reversibly dissociate or associate a proton (a hydrogen ion) to form a negatively charged anion or a positively charged cation. Molecules that dissociate protons are acids, and those that associate protons are bases. The reversibility means that a sample is always in an equilibrium with some fraction protonated and the rest deprotonated.

   HA  <=> H+ + A-   Ka = [H+][A-]/[HA]
or HB+ <=> H+ + B    Ka = [H+][B]/[HB+]

By varying the availability of protons, i.e. the acidity of the media, the equilibrium is shifted. therefore the fraction of molecules that is ionized depends on the pH. The equation for the dissociation constant Ka can be written as:

        pKa = pH + log(protonated/unprotonated) 

Where   pKa = -log[Ka]
and     pH  = -log[H+]

The pKa is often used to express the acidity/basicity of ionizable groups. From the above equation it can be derived that the pKa is equal to the pH at which the protonated and deprotonated fractions are equal. If the pH is higher than the pKa, the site is mostly deprotonated, and if the pH is lower than the pKa, the site is mostly protonated.

On the difference between LogP and LogD

The partition coefficient LogP is a constant for the molecule under its neutral form. The distribution coefficient LogD takes into account all neutral and charged forms of the molecule. Because the charged forms hardly enter the octanol phase, this distribution varies with pH. In the pH region where the molecule is mostly unionized, LogD = LogP.
In the pH region where a significant fraction is ionized, LogD becomes a function of LogP,pH and pKa. If one assumes that charged molecules do not enter the octanol at all, LogD can be expressed as: