Isoindolinone compounds active as Kv1.5 blockers identified using a multicomponent reaction approach. Issue 8 (15th April 2016)

• Record Type: Journal Article
• Authors: Kajanus, Johan; Jacobson, Ingemar; Åstrand, Annika; Olsson, Roine I.; Gran, Ulrik; Björe, Annika; Fjellström, Ola; Davidsson, Öjvind; Emtenäs, Hans; Dahlén, Anders; Löfberg, Boel; Yuan, Zhong-Qing; Sundell, Johan; Cassel, Johan; Gyll, Jonna; Iliefski, Tommy; Högberg, Ågot; Lindhardt, Emma; Malmberg, Jesper
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 8(2016)
• Page Start: 2023
• Page End: 2029
• Publication Date: 2016-04-15
• Subjects: Atrial fibrillation -- Kv1.5 -- IKur -- Isoindolinones -- Multicomponent reactions -- Structure activity relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.02.081
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.