Lead compounds combinatorial chemistry

PURPOSE AND RATIONALE In vitro testing of drug candidates and combinatorial chemistry lead to an increase of lipophilic compounds with poor solubility (Lipinsky). Poor solubility itself may lead to poor oral availability of a potential drug. The growing demand for solubility data in lead phase of drug discovery is answered by a variety of simple solubility assays, which allow the classification of a compound without real quantification (see previous section). One of the easiest way to detect saturation in a solvent is the turbidity of the solution if precipitation occurs. The turbidity caused by precipitation of a poorly soluble compound can be detected by a couple of detection methods (Van de Hulst, Hongve). Lipinsky describes the first methodology, which use UV as detection method and is able to screen hundreds of compounds a day with one instrument. 

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

The discovery of this lead compound as a potent PDF inhibitor was a result of an integrated combinatorial and medicinal chemistry approach based on the proposed generic PDF inhibitor structure. This focused chemical library was designed by Chen et al. [79], and was prepared using solid-phase parallel synthesis in which 22 amines and 24 amino acids were used as building blocks, as outlined in Scheme 23. 

One of the driving forces to apply combinatorial chemistry in drug discovery is to accelerate lead discovery and preclinical research in order to find the next drug. It is important that these combinatorial library compounds are as pure as possible when performing lead discovery screening. At this stage,... 

The number of candidate drugs has increased drastically since the introduction of combinatorial chemistry.13 One drawback is that the compounds generated often do not have favorable biopharma-ceutical and pharmacokinetic properties.1314 For example, drug candidates may be poorly soluble in water, leading to low drug concentrations in GI fluids.1314 Forty percent of late stage failures are linked to poor pharmacokinetic properties.15... 

Combinatorial approaches have been most successful when information about the target biomole cule has been considered in the design of the library. However, for many biomolecules, structural or mechanistic information is not available or does not provide sufficient insight to enable productive library design Also, lead compounds are not available for many targets, and in some cases, novel motifs for binding are desired. Under these circumstances, it is no surprise that the successful application of combinatorial chemistry has been less fre-... 

The identification of compounds with a desired property is a central pursuit in science. In the field of drug discovery combinatorial chemistry has played an increasingly important role for identification and optimization of drug leads which target therapeutically important biomolecules. For the successful implementation of combinatorial methods, new and innovative synthesis methods have been developed. Additionally, novel conceptual approaches to the design of compounds have been pursued to more efficiently generate libraries of small molecules. 

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