Lead-optimization

In order to improve the activity of the lead compound 1, the nitro group was changed to other groups. Although the non-substituted derivative 3 showed similar or slightly higher activity, we found that the chloro-derivative 4 showed much stronger activity. Optimization of substituent X with chloro-derivatives at positions 

As for substituents on the aniline ring, the ortho-methyl group was fixed, because it was essential for keeping the stability of the diamide structure. The optimization of the best position with a chlorine atom as substituent Y showed that the 4-position was the best by comparison of compounds 10-12. Other groups were introduced as substituent Y onto the aniline ring, and the results showed the tendency for a more lipophilic substituent to be preferable. Notably, the fluoroalkyl group was highly effective as exemplified with the heptafluoroisopropyl compound 

The heptafluoroisopropyl group has never been reported as a substituent in a commercial pesticide and is seldom used in pesticide research. 

The last section shows the effect of substituents (Rj, R2) on the aliphatic amide moiety. As for the aliphatic side chain, it was found that the alpha-branched alkyl side chain was essential for stabilizing the diamide structure. In the case of non-branched alkyl, the diamide derivatives tend to decompose to the corresponding phfhalimides. A variety of substituents were examined to improve the activity. As shown in Table I, the introduction of a heteroatom or a functional group increased the insecticidal activity especially a sulfur atom within the alkyl side chain markedly increased the activity. This sulfonylalkylamine is also novel as an amine residue in pesticide chemistry. In summary, flubendiamide has unique substituents as essential parts of the structure in three adjacent positions on the benzene ring, which characterizes the chemical structare of flubendiamide as totally novel. 

Flubendiamide is most effective on larvae followed by adults, but it has no ovicidal activity. In the course of extensive research on the mode of action of flubendiamide, it was determined that flubendiamide was a ryanodine receptor modulator. Flubendiamide Axes the Ca-channel of insect ryanodine receptors (RyR) in the open state, and subsequently induces calcium release from the membrane vesicle 

Once a hit is elevated to the status of a lead compound, the activity of the lead must be increased. This is accomplished by making structural modifications to the lead compound. The link between modification of a lead s structure and changes in activity is called a structure-activity relationship (SAR). As it becomes better understood, the SAR of a lead guides the medicinal chemistry team as it seeks the best methods of increasing the lead s activity. Once the lead has been adequately optimized and shows desirable properties, the lead then graduates to candidate status. Standardized safety testing in animals, called animal trials, is the next step. A more detailed discussion of the lead optimization process may be found in Chapters 11 and 12. 

The areas of lead discovery and lead optimization define the field of medicinal chemistry. A medicinal chemist typically possesses formal training in synthetic organic chemistry because medicinal chemists need to continuously make new molecules for testing in some type of assay. Although their background may be in organic chemistry, medicinal 

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Chemoinformati.cs is involved in the drug discovery process in both the lead finding and lead optimization steps. Artificial neural networks can play a decisive role of various stages in this process cf. Section 10.4.7.1). 

Chemoinformatics is primarily used for the steps of lead finding and lead optimization within the drug discovery process. In particular the following tasks are involved ... 

If small or medium libraries for lead optimization are demanded and all synthetic products are to be screened individually, most often parallel synthesis is the method of choice. Parallel syntheses can be conducted in solution, on solid phase, with polymer-assisted solution phase syntheses or with a combination of several of these methods. Preferably, parallel syntheses are automated, either employing integrated synthesis robots or by automation of single steps such as washing, isolation, or identification. The latter concept often allows a more flexible and less expensive automation of parallel synthesis. 

In the 1990s the technique of solid-phase organic synthesis (SPOS) became generally popular, but especially in the medicinal chemistry community, for lead detection and lead optimization via combinatorial techniques. The combination with microwave irradiation brought an elegant solution for the problem of the notoriously slower reactions compared to those in solution phase. 

One early step in the workflow of the medicinal chemist is to computationally search for similar compounds to known actives that are either available in internal inventory or commercially available somewhere in the world, that is, to perform similarity and substructure searches on the worldwide databases of available compounds. It is in the interest of all drug discovery programs to develop a formal process to search for such compounds and place them into the bioassays for both lead generation and analog-based lead optimization. To this end, various similarity search algorithms (both 2D and 3D) should be implemented and delivered directly to the medicinal chemist. These algorithms often prove complementary to each other in terms of the chemical diversity of the resulted compounds [8]. 

Van de Waterbeemd, H. Property-based lead optimization. In Biological and Physicochemical Profiling in Drug Research, Testa, B., Kramer, S. D., Wunderli-Allenspach, H., Folkers, G. (eds.), VHCA, Zurich and Wiley-VCH, Weinheim, 2006, pp. 25-45. 

Faller, B., Wohnsland, F. Physicochemical parameters as tools in drug discovery and lead optimization. 

Lewis, R. A. A general method for exploiting QSAR models in lead optimization. /. Med. Chem. 2005, 48, 1638-1648. 

Experimental screening established that compound 42 shown in Fig. 8.11 disrupts ZipA-FtsZ protein-protein interaction. However, previous studies suggested potential issues with toxicity associated with this class of compounds. Additionally such amine-substituted pyridyl-pyrimidines are heavily patented in the context of kinase inhibition. Both of these factors limit the scope of the subsequent lead optimization process, to transform this compound into a viable drug. Knowledge that compound 42 was a micromolar inhibitor of ZipA-FtsZ was exploited by searching for molecules that were similar in shape. 

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