Substituent set

For < z = 75-5°, < n = 44-5°. and Kn/Kl = 1-063, < is found to be 590 15, and for KjjIkj = 0-941, < is 6o° 45. It is seen that the bending of two valencies affects the disposition of the other four to only a very small extent. There are at present no published data by which this conclusion can be tested, and since the introduction of substituents in order to obtain such data from, say, measurements of electric dipole moment or electron-diffraction photographs would usually cause complications, as most substituents set up resonance of types other than that considered above, the interpretation of the results might be by no means straightforward. ... 

If there is a suitable electron-withdrawing substituent, hydrate formation may be favoured. Such a situation exists with trichloroacetaldehyde (chloral). Three chlorine substituents set up a powerful negative inductive effect, thereby increasing the 8- - charge on the carbonyl carbon and favouring nucleophilic attack. Hydrate formation is favoured, to the extent that chloral hydrate is a stable solid, with a history of use as a sedative. 

Volume and Sterio Parameters. We have noted above that sterio effects are directed quantities. This is the underlying basis of the MSI principle. In contrast to the vectorial behavior of sterio effects volume and bulk parameters are scalars. In order to clarify the difference between sterio and volume parameters we shall make use of substituent sets which are Isoohorlo (constant volume) or isosterlo (constant /). We define the quantities... 

This kind of conformational dependence has been observed for many polyaryl systems. However, no explicit consideration has been given to its implications for the interpretation of correlations even in a qualitative manner. For this type of analysis, the trityl ion series [3C ] involves less than a sufficient number of substituents. Although the benzhydryl solvolysis series has sufficient substituent sets, the change in rotation appears too small to estimate the effect quantitatively. In practice, the solvolyses of a-trifluoromethyl-diarylmethyl tosylates [29C (X,Y)J best illustrate this analysis. 

Potency of the developed candidates was measured by the log of the concentration causing a 50% inhibition in asthmatic activity. This measure is represented as pl5o- To relate pijo to molecular structure Cramer et al. (1980c) followed the two step QSAR approach. Nineteen compounds were synthesized with varying substituents, pi 50 was measured for each analog. Values for the octanol-water partition logarithm, it, and Hammett s constant, [Pg.302]

D-optimal design methods [389, 403, 655, 656] calculate the determinant of the variance-covariance matrix its value is largest for substituent sets with maximum variance and minimum covariance (linear and multiple correlation) in their physicochemical properties. An information theory approach, which leads to comparable results, has been proposed by Herrmann [657]. In some other approaches synthetic accessibility has been included as an additional selection feature [656, 658, 659]. 

Nine substituents (Set A H, Me, Bu F, Cl, Br, I, CF3 and CN) were selected as a basic set for the following qualities (i) symmetry and simplicity, (ii) freedom from conformational effects, (iii) lack of a large resonance effect, (iv) lack of any marked tendency to form hydrogen-bonds with the reaction centre. It proved possible to expand the list from 9 to 18 by making reasonable assumptions about the conformations of certain substituents, thus enabling them to be placed on the Or and v scales [Set B Set A - - Ft, PF, OMe, OEt, OPh, SMe, S02Me, CH2Ph, (CH2)2Ph]. Correlations based on Set B turned out to be superior to those based on Set A. 

Table 3 Highest Scoring 25 Designs from the Series of 432 Biased Diversity Substituent Sets from Table 2 ...

With a lead in hand, the first problem is the selection of the initial set of substituents to make. Ideally, this step involves selection of a set of substituents that represents the whole universe of factors involved in the activity of the lead compound and does so with the smallest number of compounds possible. If this step is not done well, there is a high probability that the resultant QSAR analysis will not be successful. For example, Martin and Panas present evidence that poor series design can be the cause of a failure to find a QSAR model for activity. Conversely, adoption of strategies for the proper selection of substituent sets may be all that is needed to dramatically increase the efficiency of the design process and ensure the development of QSAR models. Indeed Martinhas suggested It is the opinion of many in the QSAR field that if the only contribution of QSAR to medicinal chemistry were to emphasize the importance of objective Series design, this in itself would be a major contribution to increased efficiency. ... 

Several authors have suggested criteria for an ideal substituent set (see Martin and Panas, Wootten, et al., and Wooldridge ). The major requirements expressed by these authors are collected in the following list ... 

This set will be used to examine the criteria for an ideal substituent set a little more closely. 

The Ideal Substituent Set Should Cover All Factors That Control Activity... 

The criteria for a representative subset should be that the range covers at least one standard deviation above and below the mean for the larger substituent set. The parameter ranges for the substituents in Wooldridge s set... 

The Ideal Substituent Set Should Span Orthogonal Dimensions of Parameter Space... 

It has been demonstrated that the Topliss approach fails to meet two main criteria for an ideal substituent set wide exploration of available parameter space and a lack of colinearity in factors that are explored. Clearly, the Topliss approach is a high-risk approach that should be considered only in instances in which the specific problem of difficult synthesis is involved. In that case, several cautions should be exercised ... 

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