Example Building the Aventis Ion Channel Library

Ion channels are of potential interest in several therapeutic areas. However, appropriate high-throughput assays to test several hundred thousand compounds against a particular ion channel still lack sufficient signal-to-noise ratios [57]. Therefore, a biased ion channel library is of high interest for lead finding. 

We performed a combined 2D and 3D analysis of chemical and biological space to identify ion channel privileged chemotypes. The 2D approach was based on a collection of biologically active compounds and consisted mainly of similarity and substructure searching and of analysis of common frameworks and fragments. Our 3D approach relied on multiple ion channel pharmacophores and homology models, which were used for virtual screening. 

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. 

Picked and purchased compounds, as well as all new designed chemotype focused libraries, were assessed in terms of quality, diversity, and drug-likeness [58], The 

4 Design of Ion Channel Focused Libraries Chemical Genomics I 237 

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