Lead optimization process

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. 

Table 19.2 Key compounds is lead optimization process of cmpound (1). 

The ability of a molecule to bind to the potassium channel, hERG (human ether-a-go-go related gene), is a serious pharmacological concern and may lead to the failure to progress an otherwise active and druglike molecule during the lead optimization process. Cardiac QT interval prolongation has been associated to some extent with... 

Fig. 13.2 Schematic diagram showing the various stages and the iterative steps involved in the lead optimization process from a DMPK perspective. This schematic represents the iterative process that is an important part of the lead optimization process. The in vitro and in vivo screens refer to DMPK assays. Reprinted from [12], with permission from Taylor and Francis Group.

Experience across a wide variety of receptors with the screening of libraries designed in this way demonstrates that these design principles are effective and hits have been foimd for receptors which otherwise were considered to be difficult. Hits at a particular receptor are usually found in clusters giving an early indication of the SAR, and the same design considerations, used to produce the library, can be used in the lead optimization process. The extension of Thematic Analysis into Families B and C opens up the possibility of obtaining tractable leads in these areas as well. 

The pharmaceutical industry has pioneered in the application of computer-assisted drug design methods in product research. To a significant degree this is a consequence of the direct use of computational chemistry in enhancing the efficiency of the chemical lead optimization process. 

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 term combinatorial chemistry typically evokes images of huge libraries of molecules with members of 100,000 and even more. This type of large library is ideal for lead discovery, a situation in which a medicinal chemist is trying to cast a diverse structural net to search for activity. The lead optimization process is more specialized. The basic skeleton of the eventual candidate may already be known. Only the ideal substituents on the pharmacophore remain in question. While lead discovery and lead optimization are very different tasks, combinatorial chemistry can effectively play a role in both processes. 

The benefit of QSAR is a more efficient lead optimization process. If a good QSAR formula can be derived, the activity of leads can be approximated by calculation without... 

A successful lead optimization process is, in general, a result of careful and systematic analysis of structure-activity relationships (SAR) within an active series of compounds. The validity of the SAR obtained from screening a combinatorial library is a reflection of an accurate knowledge of the identity, purity and quantity of each library member. Also important is the ease and speed with which information can be relayed from the biological screen to the medicinal chemist. In fact, herein lies the main difference between the two techniques discussed so far. 

The lead optimization process introduces structural variations in the molecule in order to identify the best drug candidate. After a thorough evaluation of its toxicity and pharmacological activity in animal models, the molecule enters the clinical phases, when it is evaluated for tolerability, efficacy, and potential side effects on human subjects. After submittal of all the required documentation and registration to the appropriate authority (e.g. the U.S. Food and Drug Administration), the HIV protease inhibitor is ready for launching on the market. 

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