Hansch Constants A Lipophilicity Parameter

Hansch and Toshio Fujita, a postdoctoral researcher in Hansch s group, designed a parameter, ttr, to estimate the lipophilicity of an R-group.3 Hansch s parameter relies on partition coefficients to measure lipophilicity. Partition coefficients, P, are equilibrium constants describing the degree to which a molecule distributes into a biphasic mixture of two immiscible solvents. Hansch used 1-octanol and water as the model solvents because these were known to simulate the lipid membrane-cytosol interface. The partition coefficient of a molecule is defined as the ratio of a molecule s concentration in an octanol layer to its concentration in an aqueous layer (Equation 12.12). 

Partition coefficients are widely used throughout the drug discovery process. The most useful form is log P. The log P discussed here is the same as was covered in Chapter 10 as a drug selection criterion in Lipinski s rules. 

A partition coefficient is a property of a whole molecule. To define 7tr, a substituent property, Hansch compared the partition coefficient of a substituted compound with an unsubstituted compound (Equation 12.13). 

The approach of Hansch is fully analogous to the methodology that Hammett used to develop his electronic parameter. In both cases, the substituent parameter is defined as the logarithm of the ratio of two equilibrium constants (Equations 12.9 and 12.13). 

Although not perfect, Hansch s lipophilicity parameter and log P values are the most widely used parameters in QSAR studies. In addition to their effectiveness in predicting biological activity through target binding (pharmacodynamics), both parameters also affect pharmacokinetics. The pharmacokinetic applications of log P and 7r-values can be seen in Lipinski s rules and a Case Study (Carboxylate Antifungals) later in this chapter. 

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