Lipophilicity contributions

The above Hansch equations are also generally referred to as linear free energy relationships (LFER) as they are derived from the free energy concept of the drug-receptor complex. They also assume that biological activity is linearly related to the electronic and lipophilic contributions of the various substituents on the parent molecule. 

Amao MB, Cano A and Acosta, M. 2001a. The hydrophilic and lipophilic contribution to total antioxidant activity. Food Chem 73(2) 239—244. 

Thus, Tlx represents the lipophilicity contribution of the fragment X. This ttx constant takes different values according to the aliphatic or aromatic nature of the considered compound. This method, not implemented in any software, is limited by the necessity to have good log P measurements for the parent compounds for tested solutes. 

This led to the concept of fragmentation of the total molecular surface area in combination with multivariate analysis (Stenberg et al. 2001) towards predictive models of drug permeability for more complex datasets. Permeability models were established based on so-called partitioned total surface area (PTSA) descriptors. Each of the PTSA descriptors corresponds to the surface of a certain atom type, differentiated by hybridisation, which results in individual descriptors for e.g. sp3, sp2, and sp carbon atoms. The resulting permeability model based on 19 descriptors finally consisted of oxygen, nitrogen and polar hydrogen surfaces, while the main contribution for prediction of Caco-2 permeability was attributed to PSA. In addition some more lipophilic contributions... 

Lipophilicity descriptors, in particular, the atomic lipophilicity contribution La in Ghose and Crippen s system, taking into account the environment of an atom, and group lipophilicity Lg defined as a sum of contributions for a non-hydrogen atom and attached hydrogens. 

These hydrophobic substituent constants are commonly used in - Hansch analysis to encode the lipophilic behavior of the substituents the hpophiUcity of the whole molecule is obtained by adding to the lipophilicity of the unsubstituted parent compound (logPn) the lipophilic contributions of the substituents ... 

Also simply called hydrophobic fragmental constants, these are measures of the absolute lipophilicity contribution of specific molecular fragments to the lipophilicity of the molecule [Nys and Rekker, 1973 Nys and Rekker, 1974 Rekker, 1 7a Rekker, 1977b Rekker and De Kort, 1979]. 

The Broto-Moreau-Vandicke contribution method is based on hydrophobic atomic constants a measuring the lipophilic contributions of atoms, each described by its nature, neighbouring atoms and associated connectivities, thus implicitly considering some proximity effects and interactions in conjugated systems [Broto etal, 1984b]. Hydrogen atoms and correction factors are not explicitly considered. The model is defined as ... 

As one can see, even if the participation of fluorine is modest compared to hydrogen, introducing halogens like chlorine (Figure 20.35), bromine or a trifluoromethyl group induce a important lipophilic contribution (larger than the contribution of a methyl group). ... 

These are hydrophobic atomic constants a measuring the lipophilic contribution of atoms in the molecule, each described by its neighboring atoms [Ghose and Crippen, 1986 Ghose, Pritchett et al, 1988 Viswanadhan, Ghose et al, 1989]. The model for log P calculation is defined as... 

The Meylan-Howard hydrophobic model is derived from an atom/fragment contribution method providing 150 hydrophobic atomic and fragmental constants fi measuring the lipophilic contributions of atoms and fragments in the molecule, together with 250 correction factors [Meylan and Howard, 1995,1996, 2000 KOWWIN - Syracuse Research Corporation, 2008]. 

A variety of indirect methods have been developed to estimate Kow (Table 5). These include simple PPRs and SPRs (Fig. 5), as well as group additivity methods in which the lipophilic contributions of molecular fragments have been estimated (e.g., Rekker s fragment technique and UNIFAC). The existence of so many methods to estimate Kow suggests there are some fundamental difficulties in accurately determining this important parameter. As a minimum, we can expect that there will be differences in the values of a compound s Kow determined by the different techniques. This is the case, and a large literature has arisen on this subject (Andren et al., 1987 Sabljic, 1987 Eadsworth, 1986 De Voogt et al., 1988 Veith et al., 1979). 

Two effects of an alcohol additive have been mentioned so far. First, it contributes to the general formulation as a co-surfactant (slightly hydrophilic contribution for methanol and ethanol lipophilic contribution for n-butanol and longer linear alcohols) and second, as... 

It is also good to realize that properties like fragment lipophilicity contributions are additive properties, but may be very much dependent on the structural environment (Fig. 22.5). Some substitutions may have a more dramatic effect than expected. Radioactive labelling with I is quite common for biological studies. One should be aware, however, that aromatic iodination increases the log P of the compound by approximately 1 log P unit, and thus a different tissue distribution may result. An aromatic fluoro substituent has very little effect on the lipophilicity, but mainly serves in drugs to avoid oxydative biotransformation. 

Figures Log P of homologous alcohols as a function of n (number of alkyl carbon atoms) (a) n-octanol/water, slope 0.54 (lipophilicity contribution of the methylene group) (b) chloro-form/water, slope 0.62 (c) cyclohexane/water, slope 0.65 (reproduced from Figure 11 of ref. [173] with permission from Pergamon Press Ltd., Headington Hill Hall, Oxford 0X3 OBW, UK).

A modified version of the Rekker method, which has to be further evaluated, was recently published [56]. Some other atom-, bond- and group-based calculation procedures e.g. [264—271]) have been developed most of them are reviewed and critically commented in ref. [173]. The calculation of hydrophobic fields from lipophilicity contributions is discussed in chapter 9.2. 

The DARC-PELCO approach [418—423] is a simple application of a hyperstructure concept to the Free Wilson method while the approach may be appropriate for extremely large data sets, e.g. for the derivation of lipophilicity contributions from partition coefficients, it is usdess for most structure-activity analyses, due to the much too large number of variables (compare eqs. 199 and 200, chapter 8) [390, 391]. The results from Hansch, Free Wilson, and DARC-PELCO analyses have been compared with each other [421, 422, 424] no advantages of the latter approach could be seen. 

Atom-based lipophilicity contributions and molar refractivity contributions have been derived for 3D QSAR studies [266 — 269]. Audry et ai defined molecular lipophilicity potentials [914—916] for the determination of lipophilic and hydrophilic regions of a molecule. 

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