P and log

Octanol/water partition (log P) and distribution (log D) coefficients are widely used to estimate membrane penetration and permeability, including gastrointestinal absorption [74,75], BBB crossing [57,66], and correlations to pharmacokinetic properties [1], The two major components of lipophilicity are molecular size and hydrogen bonding [54], each of which has been discussed above (see Sections 5.5 and 5.6). 

According to published IUPAC recommendations, the terms hydrophobicity and lipophilicity are best described as follows [76]  

For monoprotic organic bases (BH + dissociating to B), the corresponding relationships are 

From these equations, it is possible to predid the effective lipophilicity (log D) of an acidic or basic compound at any p H value. The data required to use the relationship in this way are the intrinsic lipophilicity (log P), the dissociation constant (piCa), and the pH of the aqueous phase. The overall outcome of these relationships is the effective lipophilicity of a compound, at physiological pH, which is approximately the logP value minus one unit of lipophilicity for every unit of pH, the pit, value is below (for acids) and above (for bases) pH 7.4. Obviously, for compounds with multifunctional ionizable groups, the relationship between log P and log D, as well as log D as a function ofpH, becomes more complex [62, 65, 67]. For diprotic molecules, there are already 12 different possible shapes of log D-pH plots. Ion pairs (salts), zwitterions, and ampholytes are special cases and both measurement of log P/D and their interpretation need special attention [44, 49]. 

Traditional octanol/water distribution coefficients are still widely used in quantitative structure-activity relationship (QSAR) and in ADME/PK studies. However, alternative solvent systems have been proposed [77]. To cover the variability in biophysical characteristics of different membrane types, a set of four solvents has been suggested, sometimes called the critical quartet [78]. The 1,2-dichloroethane (DCE)/water system has been promoted as a good alternative to alkane/water due to its far better dissolution properties [79, 80], but may find little use because of its carcinogenic properties. 

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To become familiar with the application of the basic principles of the model building process by means of calculating log P and log 5 values... 

With only few exceptions, most log P programs refer to the octanol-water system. Based on Rekker s fragmental constant approach, a log P calculation for aliphatic hydrocarbon-water partitioning has been reported [96]. Another more recent approach to alkane-water log P and log D is based on the program VolSurf [97]. It is believed that these values may offer a better predictor for uptake in the brain. 

Log P and log D can be experimentally measured and computationally calculated. Both measurements and calculations can be made by a variety of methods, most of which are quite simple to perform (see following chapters). Our experience recommends, if possible, the use of both procedures. In fact the combination of theory (i.e. how things should be) with practice (i.e. how things are) enables both a better set-up of experiments and the identification of the best predictive method to be used for the chosen dataset of compounds. 

Nevertheless, this method was successfully applied by Gulyaeva et al. for the log P and log D determination of 15 P-sympatholytic drugs [56]. Another study by Welerowicz and Buszewski compared the HpophiHcity values of P-blockers obtained with a column made of a monoHthic-silica Cjg with a conventional porous silica particles Cjg as reference material [27]. A modified method was used for evaluating logP with two main differences (i) logfeg was considered rather than retention times, and (ii) benzene and butyl-benzene were used as calibration compounds. 

Regression analyses revealed systematic differences between experimental log P and log P calculations based on the summation of fragment values. These differences could be attributed to chemical characteristics of the molecules, which in turn allowed the definition of correction rules such as chain conjugation, electronegativity facing bulk or the proximity effect, which describes the presence of electronegative centers in a molecule separated by one or two carbons. Correction values needed for log P calculation were shown to represent multiples of a constant value of 0.289, which is known as the magic constant (CM). 

Tetko, I. V., Bruneau, P. Application of ALOGPS to predict 1-octanol/water distribution coefficients, log P, and log D, of AstraZeneca in-house database. 

A general definition of log P and log D, in its simplest form, can be given as the logarithm of the ratio (P or D) of the concentration of species of interest (the drug in a pharmaceutical context) in each phase, assuming the phases are immiscible and well separated prior to analysis. P is defined as the partition coefficient, whereas D is the distribution coefficient. However, the simplest form does not reveal some of the intricacies of the determination and use of these parameters, and further explanation is necessary. 

We have tried to cover some of the important aspects of the determination and use oflog P and log D parameters. Far from being exhaushve, this chapter attempted to offer some considerations and perspective in a field where, after 40 years from its beginning at the hand of Corwin Hansch et al, there does not seem to be much alternative to the balance of forces encoded by the octanol-water system to model lipophilicity. 

Molecules with a large molecular weight or size are confined to the transcellular route and its requirements related to the hydrophobicity of the molecule. The transcellular pathway has been evaluated for many years and is thought to be the main route of absorption of many drugs, both with respect to carrier-mediated transport and passive diffusion. The most well-known requirement for the passive part of this route is hydrophobicity, and a relationship between permeability coefficients across cell monolayers such as the Caco-2 versus log P and log D 7.4 or 6.5 have been established [102, 117]. However, this relationship appears to be nonlinear and reaches a plateau at around log P of 2, while higher lipophilicities result in reduced permeability [102, 117, 118]. Because of this, much more attention has recently been paid towards molecular descriptors other than lipophilicity [86, 119-125] (see section 5.5.6.). The relative contribution between the para-cellular and transcellular components has also been evaluated using Caco-2 cells, and for a variety of compounds with different charges [110, 112] and sizes [112] (see Section 5.4.5). 

Physicochemical profiling at the early discovery stage is important in the pharmaceutical industry because poor bioavailability is a leading factor in compound attrition. The ability to rapidly measure absorption properties such as solubility, log P, and log D allows promising compounds to quickly pass into exploratory development. 

To demonstrate these differences, the experimental relationship between log P and log k across a range of eluent compositions was determined for each group of analytes. The results were then used to calculate the predicted logk in each case for a theoretical model compound with log P = 5 as a hydrophobic model, for log P = 1 as a hydrophilic model, and for log P = 3 as an intermediate model. 

Propranolol, At physiological pH, the octanol concentration of the protonated jjj-blocker propranolol is 25% of the concentration of the neutral species (based on its aqueous pKa, the reported log P, and log P from 0.15 M sodium chloride, (Table IV). 

Virtual Filtering In Silica Prediction of log P and log D 93 Table 5.1 Non-exhaustive list of software packages which use one of the methods described. 

In contrast fast in silico predictive tools for log P and log D (using estimated pKa values) from the 2D molecular structures can be very useful to enrich the molecular... 

In a study of anabolic steroids, the activity (log BR) of compounds of structure 12.b was found to depend on lipophi-licity, log P, and its square, (log P)2. Based on the data in the following table, perform a multiple linear regression relating activity to log P and (log P)2. What is the predicted... 

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