A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D‐Shaped Triquinazine Ring System from Chemical Space,Angewandte Chemie International Edition

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A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D‐Shaped Triquinazine Ring System from Chemical Space
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2020-09-28 , DOI: 10.1002/anie.202012049
Kris Meier ₁ , Josep Arús-Pous ₁ , Jean-Louis Reymond ₂

Affiliation

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.

中文翻译：

来自化学空间的具有手性3D形状的三喹嗪环系统的强效选择性Janus激酶抑制剂

生成的数据库（GDB）遵循化学稳定性和合成可行性的简单规则，列举了数十亿个可能的分子。对GDB的研究表明，许多通常包含四级中心的手性3D形环系统从未被用于药物设计。本文显示通过使用对苯二酚对映选择性合成的例子，这种环系统可用于药物化学，该对苯二酚是一种衍生自角三喹烷的新型手性哌嗪类似物。它被用于设计Janus Kinase 1的纳摩尔选择性抑制剂，并与市售药物Tofacitinib有关，该药物可用于治疗自身免疫性疾病。

更新日期：2020-09-28

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