Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 4, Pages 2074-2077Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202012049
Keywords
chemical space; drug design; heterocycles; inhibitors; synthetic methods
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Funding
- Swiss National Science Foundation [200020 178998]
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The study discovered that many chiral, 3D-shaped ring systems, often containing quaternary centers, in the generated databases have not been explored for drug design. By using triquinazine as an example, a nanomolar and selective inhibitor of Janus Kinase 1 was designed, which is related to the marketed drug Tofacitinib used for treating autoimmune diseases.
The generated databases (GDBs) enumerate billions of possible molecules following simple rules of chemical stability and synthetic feasibility. Exploring the GDBs shows that many chiral, 3D-shaped ring systems, often containing quaternary centers, have never been exploited for drug design. Shown herein is that such ring systems can be useful for medicinal chemistry by using the example of the enantioselective synthesis of triquinazine, a novel chiral piperazine analogue derived from angular triquinane. It is used to design a nanomolar and selective inhibitor of Janus Kinase 1 and is related to the marketed drug Tofacitinib, which is useful for treating autoimmune diseases.
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