Isoindolinone compounds active as Kv1.5 blockers identified using a multicomponent reaction approach

Journal: Bioorganic & Medicinal Chemistry Letters
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Author(s): Johan Kajanus, Ingemar Jacobson, Annika Åstrand (b., Roine I. Olsson, Ulrik Gran, Annika Björe, Ola Fjellström (a., Öjvind Davidsson, Hans Emtenäs, Anders Dahlén, Boel Löfberg, Zhong-Qing Yuan, Johan Sundell, Johan Cassel, Jonna Gyll, Tommy Iliefski, Ågot Högberg, Emma Lindhardt, Jesper Malmberg

A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be achieved despite a relatively high logD. The compounds were synthesized using the Ugi reaction, in some cases followed by Suzuki and Diels–Alder reactions, giving a diverse set of compounds in a small number of reaction steps.