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

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• 作者：Johan Kajanus^a ; ; Ingemar Jacobson^a ; Annika Å ; strand^b ; Roine I. Olsson^b ; Ulrik Gran^a ; Annika Bjö ; re^a ; Ola Fjellströ ; m^a ; Ö ; jvind Davidsson^a ; Hans Emten&auml ; s^a ; Anders Dahlé ; n^a ; Boel Lö ; fberg^a ; Zhong-Qing Yuan^a ; Johan Sundell^a ; Johan Cassel^a ; Jonna Gyll^a ; Tommy Iliefski^a ; Å ; got Hö ; gberg^a ; Emma Lindhardt^a ; Jesper Malmberg^b
• 关键词：Atrial fibrillation ; Kv1.5 ; IKur ; Isoindolinones ; Multicomponent reactions ; Structure activity relationship (SAR)
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：26
• 期：8
• 页码：2023-2029
• 全文大小：2413 K

文摘

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.