Search parallel synthesis

As stated before, PGVL is too large to be fully enumerated practically. Therefore our strategy is to find a way to focus in a just-in-time manner on much smaller sub-regions ( 104) of PGVL for subsequent on-the-fly enumeration followed by standard similarity search against the same query molecule. It is intuitively evident that a virtual compound space built from parallel synthesis reaction protocols has inherent array structures in the form of implicit arrays of related just-in-time enumerated compounds, even if those compounds do not have their molecular structures yet enumerated at the time this inherent array structure is exploited. 

Are certain scaffolds privileged because they are heavily explored, or do they inherently possess favourable characteristics for the discovery of new drugs The two explanations appear equally likely. One of the greatest achievements of combinatorial chemistry is the testing of this hypothesis by the exploration of relatively uncharted chemical space. Thanks to parallel synthesis, enough library members can be made to evaluate the new scaffold with reasonable confidence. In addition to this curiosity-driven search of new scaffolds, another important motivation is the pressing need to source novel and patentable compound classes that do not overlap with those of competitors. 

In a search for new isoxazole-based liquid crystalline compounds, a 22-member library of 3,5-diaryl isoxazoles 628 was prepared by parallel synthesis on solid phase (Rink resin) through 1,3-dipolar cycloaddition of supported phenylacetylene units with suitable aryl nitrile oxides generated in situ from hydroxyiminoyl chlorides. Cleavage from the resin under acidic conditions allowed the generation of the cyano moiety <2004TL2277>. 

A new approach to obtain increased diversity in the search for new lead compounds called kombiNATURik has been co-developed by the German companies AnalytiCon and Jerini Bio Tools. The kombiNATURik program starts from natural compounds which are further diversified by solid-support chemistry introducing e.g. peptide or carbohydrate moieties. KombiNATURik libraries generally comprise several hundreds to thousands of single molecules derived from multi-parallel synthesis. 

Naerum et al. [133] used topological pharmacophores to search for novel glycogen synthase kinase-3 inhibitors at Novo Nordisk. Using virtual screening based on the CATS descriptor, a novel chemotype with activity against GSK-3 was identified. After parallel synthesis around the identified motifs, interesting inhibitors with GSK-3 activity <1 [xM were found (Figure 12.11a). 

Parallel synthesis is now established as an integral component of lead optimisation methodology and increasing numbers of reports on the use of this approach in medicinal chemistry programmes are appearing in the literature. Jarvest et al. [12] explored the structure activity relationship at the 2-position of benzoxazi-nones in the search for inhibitors of herpes simplex virus-1 protease. Reaction of anthranilic acids with excess isocyanate or chloroformate afforded the 2-amino or 2-alkoxy substituted derivatives (Figure 5). 

In the search for new dmgs, most pharmaceutical companies have abandoned the natural product. Switzerland is a case in point out of twenty start-up and spin-off pharmaceutical companies, seven make use of parallel and combinatorial synthesis, which is much less expensive than the search for bioactive natural products and is free from obligations toward the countries holding the rights for the germ plasm. Only one of the new Swiss conq)anies relies on natural products, merely raw extracts for veterinary use (L EppIatenier 2000). 

In the same publication, a method for the parallelization of TAP experiments was also indicated. It was stated that ...high-throughput transient kinetics carried out in addition to high-throughput catalyst synthesis and testing both accelerate the search for new catalytic materials and bring fundamental insights into reaction mechanisms. ... 

Explorations of new electrochemical routes to traditional as well as specialty chemicals via electro-organic synthesis have given rise to a search for more efficient electrochemical reactors. The radial flow reactors or cells show promise compared to the conventional parallel plate configurations. A typical radial flow reactor is schematically shown in Fig. 39, which includes the... 

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