Parameters lipophilicity

The amino group is readily dia2oti2ed in aqueous solution, and this reaction forms a basis for the assay of sulfas. Aldehydes also react to form anils, and the yellow product formed with 4-(dimethylamino)hen2a1dehyde can be used for detection in thiu-layer and paper chromatography. Chromatographic retention values have been deterrnined in a number of thiu layer systems, and have been used as an expression of the lipophilic character of sulfonamides (23). These values have corresponded well with Hansch lipophilic parameters determined in an isobutyl alcohol—water system. 

HPLC INVESTIGATION OF pH DEPENDENCY OF THE LIPOPHILICITY PARAMETER OF PARABENS... 

However, Clog P and, more generally, Hpophilidty descriptors referring to octanol-water are not the only lipophilicity parameters to be taken into account As mentioned above, isotropic and anisotropic Hpophilidty values gave rise to two different Hpophilidty scales for ionized compounds and thus it is recommended to test both of them (after checking the absence of any coHnearity) when looking for a QSAR model involving ions. 

A thorough review, even with a very superflcial mention of the vast literature on ADME, QSPR and QSAR applications involving the use of lipophilicity, would be a daunting task and it is far beyond the scope of this chapter. However, it is no surprise that three international conferences, in recent years, have been specifically dedicated to this topic, and that the development of newer and faster screening methods, in some cases seeking to produce alternative lipophilicity parameters to the classical or nonclassical log Pod determinations are still an active area of interest [6]. 

Note that the lipophilicity parameter log P is defined as a decimal logarithm. The parabolic equation is only non-linear in the variable log P, but is linear in the coefficients. Hence, it can be solved by multiple linear regression (see Section 10.8). The bilinear equation, however, is non-linear in both the variable P and the coefficients, and can only be solved by means of non-linear regression techniques (see Chapter 11). It is approximately linear with a positive slope (/ ,) for small values of log P, while it is also approximately linear with a negative slope b + b for large values of log P. The term bilinear is used in this context to indicate that the QSAR model can be resolved into two linear relations for small and for large values of P, respectively. This definition differs from the one which has been introduced in the context of principal components analysis in Chapter 17. 

Figure 12 Correlation of lipophilicity parameter (it) for substituent R5 of compounds 1a,d-f,h, j, k, and 2a-o with their antagonistic activity. p < 0.0001.

The C5+, and smeta values were experimentally determined, and the ASA, vdW and logP (o/w) were determined in MOE. [7t = lipophilicity parameter o+ = Hammett constant for ben-zylic cations Esmeta = Tafts steric parameter ASA = water accessible surface area vol = van der Waals volume logP (o/w) = log of the octanol/water partition coefficient.]... 

Among the large number of existing lipophilicity parameters [31], the descriptor frequently estimated by in silica methods is the partition coefficient of a solute between 1-octanol and water, expressed as log Poet [32]. However, lipophilicity determination in different solvent systems, such as alkane/water system, proved its utility in (Q)SAR studies and therefore some predictive methods also emerged in this field. Many publically available databases include numerous experimental values collected through the literature the quality of the experimental data represents the cornerstone of most of the models developed to predict lipophilicity. 

A modification of the atomic approach was also proposed by Gaillard et al. using molecular lipophilicity potential (MLP) as a 3D source of two lipophilicity parameters calculated from the water-accessible surface, namely a hydrophobic parameter expressed as the sum ofthe positive lipophilicity potential (EM LP+) and a polar parameter expressed as the sum of the negative lipophilicity potential (EMLP—)... 

The function of a transport parameter is to model the transfer of the bas from the aqueous phase to biomembrane and bas receptor. The transport parameter is frequently also referred to as a hydrophobicity or lipophilicity parameter, the former term is no doubt preferred by pessimists and the latter by optimists. Unfortunately, there has been no attempt at the standardization of nomenclature in this field (A rose by any other name. ..). As is usually the case under these circumstances far too much heat and very little light results. 

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. 

Lipophilicity parameters, whether included as it- values or log P, are often included twice once to the first power and again to the second power. This accommodates the common parabolic relationship between biological activity and lipophilicity (log P) (Figure 12.3). The curve will have a maximum at a lipophilicity value that balances the molecule s need to be both sufficiently polar to dissolve in the cytosol and nonpolar enough to enter and cross a cell membrane. 

Lipophilicity parameters are often found in a squared form in Hansch equations. The following Hansch equation contains a squared steric term ( ). Is this surprising Why or why not ... 

Examples for compounds are given in Figure 8.1, and the regression analysis equation is provided below for the QSAR of triazine derivatives in photosynthesis (Draber, 1992). The inhibitory potency expressed as a pl50 value is equal to a lipophilicity parameter tt (log of the partition coefficient P), an electronic substitution parameter a (the Hammett constant) and to a lesser degree to a steric component Es (the Taft constant). 

Fig. 2.4 Relation between the lipophilicity of compounds 1-7 and their other properties. (A) Variation of log P p with the number of methylene groups (n). (B) Variation of log P p with the number of methylene groups. (C) Linear regression between log NMR slope and lipophilicity parameters in the system liposome-water. (Reprinted from Fig. 3 of ref. 48 with permission from Kluwer Academic/Plenum Publishers.)...

Tab. 4.11 Lipophilicity parameters and measured and calculated 1AM capacity factors for various compounds. (Reprinted from Tab. 1 of ref. 42 with permission from Elsevier Science)...

The lipophilicity parameter, log Kow, is generally greater than zero for CYP substrates or inducers. This is attributable, at least in part, to the fact that in most eukaryotic cells P450 is embedded in a phospholipid membrane across which a substrate has to travel (Lewis et al., 2001). 

These compounds are able to diffuse through both the membrane and aqueous pores and/or tight junctions. The global absorption rate constant is described by the sum of two absorption rate values which represent two different pathways the penetration into the lipoidal membrane, and across the aqueous pores. B, I , a, and o are constants that depend on the experimental technique used to obtain the absorption rate constants, P is the lipophilicity parameter, and km and kp are the asymptotic values for the membrane and the paracellular way, respectively. For compounds with a molecular weight higher than 250 Da the contribution of the aqueous pathway is negligible, collapsing the equation to the one hyperbola model already described for colon. 

The micelle-solubilized fraction is not available for absorption. The bilinear equation is in this case applicable to correlate absorption rate constant values and lipophilicity parameters ... 

The substitution pattern of the 4-aromatic residue is also important for the activity, the ortho-substitution being the best one in terms of potency and selectivity. A Hansch analysis on a series of ortho-derivatives has shown a significant correlation between calcium antagonist activity and steric hindrance of the substituent, while no relationship was found for either electronic or lipophilic parameters [3]. The best SAR correlation was obtained when the B1 steric parameter (the Verloop parameter) was introduced into the analysis [4]. The calcium channel-blocking activity increases as B1 increases, which probably indicates that steric hindrance in the ortho-position is required to fix the dihydropyridine structure into a favorable conformation in which the aromatic group is approximately perpendicular to the dihydropyridine ring (Fig. 7.12). 

Alternative detection methods such as mass spectrometry, ELS or nitrogen detector are in most cases inappropriate due to the octanol saturated aqueous media. An alternative is the use of standard HPLC reversed phase gradient systems (Valko). These systems do not represent true octanol water partitions, but are also good lipophilicity parameters by themselves. 

To characterize the substituents (the X block) a set common substituent parameters were compiled from the literature. These parameters were as (Taft inductive parameter), trp (Hammett parameter for para substituents), F and R (Swain-Lupton dual substituent parameters), Es and Esc (Taft steric parameters), van der Waals radius, L, Bv B2, B3, (Verloop sterimol parameters), MR (molar refractivity), and n (Hansch lipophilicity parameter). Data are given in Refs. [1,19] and are not reproduced here. 

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