Lipophilicity fragmental approache

The obvious drawback of this method is that the parent solute, at least, has to be available or must be synthesized, and its log P value has to be determined experimentally. Nys and Rekker therefore developed a method known as the fragmental constant approach, which is based on the additivity of fragment contributions to the molecular lipophilidty [7] (see Eq. (9), where a( is the inddence of fragment i, fi the lipophilic fragment constant, Ci a corredion factor, and the frequency of Cm). 

R. F. Rekker and R. Mannhold, Calculation of Drug Lipophilicity. The Hydrophobic Fragmental Approach, VCH, Weinheim, 1992, p. 112. 

Commonly used methods are based on fragment constants. The fragmental approaches are based on a simple addition of the lipophilicity of the individual molecular fragments of a given molecule. Three commercially... 

Lipophilicity in particular, as reflected in partition coefficients between aqueous and non-aqueous media most commonly water (or aqueous buffer) and Z-octanol,has received much attention [105,141,152,153,176,199,232,233]. Logic )W for the octanol-water system has been shown to be approximately additive and constitutive, and hence, schemes for its a priori calculation from molecular structure have been devised using either substituent tt values or substructural fragment constants [289, 299]. The approximate nature of any partition coefficient has been frequently emphasized and, indeed, some of the structural features that cause unreliability have been identified and accommodated. Other complications such as steric effects, conformational effects, and substitution at the active positions of hetero-aromatic rings have been observed but cannot as yet be accounted for completely and systematically. Theoretical statistical and topological methods to approach some of these problems have been reported [116-119,175,289,300]. The observations of linear relationships among partition coefficients between water and various organic solvents have been extended and qualified to include other dose-response relationships [120-122,160,161,299-302]. 

The lipophilic behaviour of organic compounds 1. An updating of the hydrophobic fragmental constant approach. Quantitative Structure-Activity Relationships, 17, 517-536. 

Rekker, R. F. and R. Mannhold. 1992alculation of Drug Lipophilicity, the Hydrophobic Fragmental Constant Approach. Weiheim, Germany VCH. 

Alternatively, the second of these two modules can be left out, as in 122 and 123 (Figure 9.27). Here, the lactam module and the lipophilic ring module on the other end are connected by a flexible alkyl linker, leading to structures that are reminiscent to those constructed by fragment-based approaches, thus forming a third inhibitor subfamily (Figure 9.27). 

In order to extend the CoMMA approach to account for the lipophilicity of the molecule, the - Leo-Hansch hydrophobic fragmental constants [Abraham and Leo, 1987] have been proposed as a set of atomic lipophilic weights for the calculation of lipophilic molecular multipole moments (hydropoles) [Burden and Winkler, 1999a]. 

Mannhold, R., Rekker, R.F., Dross, K., Bijloo, G.J. and de Vries, G. (1998b). The Lipophilic Behaviour of Organic Compounds 1. An Updating of the Hydrophobic Fragmental Constant Approach. Quant.Struct.-Act.Relat., 17,517-536. [R]... 

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