A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D-Shaped Triquinazine Ring System from Chemical Space

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.

Automated summary

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.