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

Autor: Kajanus J; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Jacobson I; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Åstrand A; Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Olsson RI; Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Gran U; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Björe A; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Fjellström O; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Davidsson Ö; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Emtenäs H; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Dahlén A; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Löfberg B; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Yuan ZQ; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Sundell J; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Cassel J; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Gyll J; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Iliefski T; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Högberg Å; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Lindhardt E; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden., Malmberg J; Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Apr 15; Vol. 26 (8), pp. 2023-9. Date of Electronic Publication: 2016 Mar 02.
DOI: 10.1016/j.bmcl.2016.02.081
Abstrakt: 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.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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