The Topliss Tree

Topliss makes it very clear that the schemes presented are not expeaed 

Takayama and Fujinami subsequently prepared seven 3,5-disubsdtuted derivatives, the most potent of which was the 3,5-dibromo (p/50 = 5.77) derivative, which was also the most potent in the whole study. Thus, if the Topliss approach had been followed, 14 compounds, not 61 compounds, would have been prepared, a resource reduction of 77%. Of course, less certainty and thus higher risk would have been involved. For example, no ex- 

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  

The operational scheme should be applicable to the biological test used for ranking. 

Follow-up in the form of a well-designed set based on the constraints learned during the Topliss approach is absolutely required to reduce risk of missing an important compound to an acceptable level. 

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FIGURE 12.6 A portion of the Topliss tree for aromatic substitution... 

Topliss tree The Topliss tree is an empirical decision scheme for a stepwise aromatic substituent selection and lead optimization that is guided by the supposed influence on potency due to the hydrophobic, electronic, and steric effects of the substituents. 

In the pyranenamine series, choice among the "next" appropriate derivatives had been made difficult by experimental uncertainty surrounding the relative potency values, and as a result Table I contains information about most of the nodes In the "Topliss tree", not merely an individual branch. In fact, the A-OH derivative, the most potent of the nineteen, can be reached via the tree only by taking the apparent "wrong turn" at two of three nodes. Strict adherence to the decision model would have produced nothing but derivatives less active than the starting unsubstituted compound. 

Fig. 2.7. Illustration of the Topliss tree process for compound selection L, E, and M represent less, equal, and more active respectively (after Topliss and Martin 1975, with permission of Academic Press).

Nevertheless, Hansch analysis revolutionized drug molecule optimization and directly led to two other strategies for molecule optimization the Free-Wilson method and the Topliss decision tree. 

Topliss Decision Tree Method. This method is quicker and easier to use than the Hansch method. The Topliss scheme is an empirical method in which each compound is tested before an analog is planned, and is compared in terms of its physical properties with analogs already planned. Like the Free-Wilson method, the Topliss decision tree is no longer extensively used. The 2D- and 3D-QSAR methods are gradually supplanting the ID methods. 

Figure 4.7 The Topliss decision trees for (a) an unfused aromatic ring and (b) an aliphatic side chain. (L = significantly lower activity, E = about the same activity and M = significantly greater activity). Reproduced by permission of Taylor and Francis Ltd. from the Journal of Medicinal Chemistry 15, No. 101006 (1972), http //www.tandf.co.uk/journals. Utilisation of Operational Schemes for Analog Synthesis in Drug Design by J G Topliss...

Figure 4.8 A hypothetical example of the use of the Topliss decision tree. The compounds are synthesized in the order A, B, C,. .. etc. It should be realized that only some of the compounds synthesized will be more potent than the original lead A...

The Topliss decision tree does not give all the possible analogues but it is likely that a number of the most active analogues will be found by this method. 

Steinbaugh, B.A., Hamilton, H.W., Vara Prasad, J.V.N., Para, K.S., Tummino, P.J., Fergusson, D., Lunney, E.A., and Blankley, C.J. 1996. A topliss tree analysis of the HlV-protease inhibitory activity of 6-phenyl-4-hydroxy-pyran-2-ones. Bioorganic and Medicinal Chemistry letters, 6(10) 1099-104. 

The right substituent choice minimahzes the number of test compounds that have to be synthesized to insnre a significant space volume. This point represents a 3D extension of the Craig plot discnssed by Craig" and by Anstel. In this context, the decision tree proposed by Topliss allows a fast identification of the snbstitnents associated with the highest potency. Application examples of the Topliss scheme are discussed by Martin and Dnnn. ... 

FIGURE 8.2 A Topliss Tree for aliphatic side chain substitutions. The Topliss schemes were constructed by consideration of hydrophobic and electronic factors and are designed such that the optimum substituent maybe found as efficiently as possible. It is assumed that the methyl substituted compound has been made, tested, and compared to the unsubstituted compound. There are three possibilities the analogs will have less (L), equal (E), or more (M) activity and this determines which branch of the tree should be followed next. 

An essentially nonmathematical approach to utilizing the basic Hansch concepts to help design drugs was developed by Topliss (1977). It has been called a decision tree (Fig. 1-10), by which a lead compound can be efficiently optimized without the use of computers. By preparing several well-chosen analogs of a lead compound, the next several... 

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