Small Focused Libraries

The issue of parallel versus sequential synthesis using multimode or monomode cavities, respectively, deserves special comment. While the parallel set-up allows for a considerably higher throughput achievable in the relatively short timeframe of a microwave-enhanced chemical reaction, the individual control over each reaction vessel in terms of reaction temperature/pressure is limited. In the parallel mode, all reaction vessels are exposed to the same irradiation conditions. In order to ensure similar temperatures in each vessel, the same volume of the identical solvent should be used in each reaction vessel because of the dielectric properties involved [86]. As an alternative to parallel processing, the automated sequential synthesis of libraries can be a viable strategy if small focused libraries (20-200 compounds) need to be prepared. Irradiating each individual reaction vessel separately gives better control over the reaction parameters and allows for the rapid optimization of reaction conditions. For the preparation of relatively small libraries, where delicate chemistries are to be performed, the sequential format may be preferable. This is discussed in more detail in Chapter 5. 

What The chemistry required for a focused library synthesis may be extremely robust and assessed, but even less robust synthetic schemes can be adapted to accommodate the needs of a small focused library synthesis. All the library components are inspired by the structural information available, but nevertheless they must provide a detailed exploration of the structure-activity relationship for analogues of the parent structure. 

A compromise between large unbiased and small focused libraries has become popular, especially for pharmaceutical applications. These biased-targeted libraries are not inspired by a precise structural information, but rather by general information regarding similar classes of targets (e.g., kinases or 7-transmembrane receptors) or by the desired activity-unrelated profile that a drug must possess (e.g., the molecular weight, the partition coefficient, the water solubihty, and other physicochemical properties). Their main properties are fisted in Fig. 5.6. 

Four recent examples of computational selection of the most similar compounds in a virtual library set will be now reviewed. Either a few different lead stmctures were available as starting points for the selection or a detailed knowledge of the target allowed to design and select a medium/small focused library. 

The library was tested using a known competition assay (142), and binding activities for the 30 pools were acquired. While the pool complexity was low, as was therefore the possibility of false positives/artifacts, the extreme similarity of all the library components with known calcium channel blockers (compare the monomers in Fig. 7.19 leading to nifedipine. Mi = A, M2 = K, M3 = T, with all the others) meant a constant level of activity was to be expected for all pools. For such a small focused library, parallel synthesis would probably have been more suitable to acquire a refined SAR, but we will see how iterative deconvolution succeeded anyway in both identifying active individuals and showing significant activity differences for different pools. The screening results are reported in Table 7.1. Five pools showed activity > 1 xM, 12 pools had an activity between 100 nM and 1 xM, and 11 pools were active between 10 and 100 nM. Two pools showed an activity around 7-8 nM They both contained methyl acetoacetate (M2, K) as well as 2-fluorobenzaldehyde (M3, P) and 2-nitroben-zaldehyde (M3, T), respectively. 

Fully automated instruments with low-medium throughput, typically a few hundred compounds per week for one- to three-step synthetic schemes in solutions, are suitable for small, focused libraries where more challenging reaction conditions such as heating, using reactive intermediates, or when inert atmospheres are needed. These instmments are also suitable for intermediate steps in the construction of larger libraries. For example, monomer rehearsal can be performed by reacting a common intermediate with various monomer candidates, and a small model library may be prepared. Even chemistry assessment may be tackled with these instmments. 

In addition to natural product sources, chemical compound libraries are used frequently in the drug discovery process. These libraries can range from small, focused libraries specifically synthesized with a particular target in mind to massive, randomly generated libraries. While there is still the problem of deconvolution of an active library, synthetically generated libraries do have a few advantages over natural product extract mixtures. There are typically equal... 

A new approach termed Biology Oriented Synthesis (BIOS) has been developed recently by Waldmann et alf This approach is based on the structural similarity between small bioactive molecules on the one side and their receptors, that is proteins, on the other side as well as on the complementarity of both. BIOS employs compound classes from biologically relevant regions of chemical space, for example natural product or drug space, to select scaffolds as starting points for the design and synthesis of small focused libraries with limited diversity. In this respect BIOS provides a conceptual alternative to other approaches... 

Recently, Nakagawa and co-workers (06BMCL5939) (Scheme 13) prepared a small focused library of edaravone derivatives. Edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one), also known as... 

Cooper TWJ, Campbell IB, Macdonald, SJF (2010) Factors Determining the Selection of Organic Reactions by Medicinal Chemists and the Use of These Beactions in Arrays (Small Focused Libraries). Angew Chem Int Ed 49 8082-8091... 

Cooper TWJ, Campbell IB, MacDonald SJF. Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (small focused libraries). Angew. Chem. Int. Ed 2010 49(44) 8082-8091. 

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