McGowan’s volume

Several research groups [70-74] studied symmetrical and non-symmetrical cyclic urea derivatives extensively. Nugiel et al. [70] reported the enzyme inhibitory activity (Ki) of symmetrical cyclic urea derivatives in which the characteristic benzyl Pi/Pj moiety was replaced by novel Pi/Pj substituents (16). P2/P2 substituents were either benzyl or CH2-cyclopropyl groups. The activity was shown to be significantly correlated with the McGowan s volume of Pi/P i-substituent and two indicator variables [ 14]. 

In this equation E (R2) is the excess molar refraction, S (tt ) is the solute dipolarity-polarizabiUty, A (2a ) and B(2 3 ) are the solute H-bond acidity and basicity, respectively, and Vis the McGowan characteristic volume (in cm mol /100). The solute size, V, (molecule favors octanol) together with solute H-bond basicity, B, (favors water) are the dominating parameters of this equation. The use of Bo(2P ) resulted in equation... 

Zhao and coworkers [53] also constructed a linear model using the Abraham descriptors. The MLR model possesses good correlation and predictability for external data sets. In this equation, E is an excess molar refraction (cm3/mol/ 10.0) and S the dipolarity/polarizability, A and B are the hydrogen bond acidity and basicity, respectively, and V is the McGowan characteristic volume (cm3/ mol/100). The large coefficients of A and B indicate too polar molecules having poor absorption. 

Here E is the solute excess molar refractivity, S is the solute dipolarity/ polarizability A and B are the overall or summation hydrogen-bond acidity and basicity, respectively and V is the McGowan characteristic volume lower-case letters stand for respective coefficients which are characteristic of the solvent, c is the constant. By help of sfafisfical methods like the principal component analysis and nonlinear mapping, the authors determined the mathematical distance (i.e., measure of dissimilarify) from an IL fo seven conventional solvents immiscible with water. It appears that the closest to the IL conventional solvent is 1-octanol. Even more close to IL is an aqueous biphasic system based on PEG-200 and ammonium sulfate (and even closer are ethylene glycol and trifluoroethanol, as calculated for hypofhefical water-solvenf sysfems involving fhese solvenfs). 

There is very little problem in calculating an acceptable measure of solute size. Simple calculations of either molecular volume or area based on either Bondi s (Bondi, 1964) or McGowan s (Abraham, 1987) methods work almost as well as those derived from molecular mechanics and quantum chemistry (Leo, 1993). When volume in cubic Angstroms is used, V is normally scaled by 0.01 to produce a coefficient comparable to the others in the equation polarity/polarizability. 

Pj is the overall hydrogen bond basicity, and Vx is the McGowan s characteristic molecular volume [(cm3/mol)/100]. Hydrogen bond interactions between acidic and basic sites in the compound, x P , are incorporated in Equation (3.42). 

In Eq. (11.13) Vx is the so-called McGowan s characteristic volume calculatable simply from the molecular structure, rr" is the dipolarity/polarizability of the analyte which can be determined by gas-chromatographic and other measurements, is... 

This equation is based on Abraham s solvation equation which uses five molecular descriptors excess molar refraction (F), solute polarity/polarizability (S), McGowan characteristic volume (V), solute overall acidity (A) and basicity (B). The steric (size/shape) descriptors E, S and V have a positive effect on oral absorption, while the descriptors related to H-bonding, A and B, have a negative effect. The model accounts for 74% of the variance (r ) in the data and the predictions have a 14% standard error (i). This is nearly as good as it gets, since the experimental biological variance is ca. 15%. 

The McGowan s characteristic volume is frequently used as a measure of the cavity term in —> linear solvation energy relationships. 

In an excellent paper, Zhao et al. [29] assembled a carefully reviewed literature set of human absorption data on 241 drugs. They showed that a linear regression model built with 5 Abraham descriptors could fit percent human absorption data reasonably well (r2 = 0.83, RMSE = 14%). The descriptors are excess molar refraction (E), polarizability (S), hydrogen bond acidity (A), hydrogen bond basicity (B), and McGowan volume (V), all related to lipophilicity, hydrophilicity, and size. In a follow-on paper, data on rat absorption for 151 drugs was collected from the literature and modeled using the Abraham descriptors [30]. A model with only descriptors A and B had r2 = 0.66, RMSE = 15%. 

Hydrophobic parameters are mostly experimentally obtained log P or calculated log P (C log P), where P is the octanol-water partition coefficient. n is the hydrophobic constant of the substituents. The electronic parameters (Hammett constants) a, a and appHes to substituent effects on aromatic systems and Taft s a appHes to ahphatic systems. Steric parameters are Tafts steric parameter Es, McGowan volume MgVol, van der Waals volume Vw, molecular weight MW. Verloop s sterimol parameters Bl, B5 and L... 

I would like to thank Paul Upchurch, Alistair J. McGowan, and Claire S. C. Slater for organising this volume and the invitation to participate in both the conference... 

---