Chemical focused libraries

Fig. 3-7. Evaluation of a focused library of 71 DNB-dipeptide CSPs for enantioseparation of the test racemate 8. (Reprinted with permission from ref. [86], Copyright 1999, American Chemical Society.)...

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. 

There are two major classes of libraries for drug discovery diverse libraries for lead discovery and focused libraries for lead optimization. Lead discovery libraries emphasize diversity while lead optimization libraries prefer similar compounds. The purpose of lead discovery libraries is to find lead matter and to provide potential active compounds for further optimization. Without any prior knowledge about the active compounds for a given target, it is reasonable to start with a library of enough chemical space coverage to demarcate the biologically relevant chemical... 

A practical solution to this problem, called GLARE (Global Library Assessment of REagents) (4), has been developed and validated in our laboratories and is explained in this chapter. We will focus on a specific chemical combinatorial library to illustrate the workflow and the use of the software. 

Focused libraries. A basic idea behind the design of diverse libraries has been that representative coverage of global chemically diversity would ensure that libraries could produce hits against many different therapeutic targets and thus be... 

In the selected example by Lam et al. [101] many peptide libraries were prepared using the mix and split technique and tested in different on-bead screens. Incomplete libraries were tested (the population of most of them was more than a million compounds), and the positive structures were exploited through focused libraries. Some libraries were screened against an anti-insulin monoclonal antibody tagged with alkaline phosphatase, which allowed an enzyme-linked colorimetric detection. Only the beads bound to the murine MAb showed a tourquoise color, while the vast majority remained colorless (details of the technical realization of the assay can be found elsewhere [101, 102]). The chemical structure linked to the positive beads was then easily determined via Edman degradation of the peptide sequences. 

Design of Ion Channel Focused Libraries Chemical Genomics 233... 

Scaffold proposals were collected and reviewed according to privileged ion channel motifs, chemical feasibility, and fit to our multiple pharmacophores. Building block selection, virtual library design, and filtering yielded small virtual libraries suitable for automated solution-phase synthesis. All synthesized compounds were finally purified and characterized prior to addition to our focused library. 

The increasing information in biological and chemical space and its effective transformation into a knowledge-driven ion channel focused library may foster a paradigm shift in lead identification. 

Figure 4.1 Chemical diversity and similarity primary and focused libraries in the chemical space.

When The combinatorialization, usually in small solution- or solid-phase arrays, of the planned synthesis is not particularly demanding for focused libraries. Moreover, an active compound from a primary library is often the stmctural information around which the focused library has been designed so that a detailed chemical assessment has already been performed. The use of focused libraries should become more and more frequent given the simplicity of their synthesis and the significant impact they may have on the progression of many projects. 

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