title: Isoindolinone compounds active as Kv1.5 blockers identified using a multicomponent reaction approach.
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.
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Kajanus
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Jacobson
authors.affiliation: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Åstrand
authors.affiliation: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Roine I
authors.initials: RI
authors.lastname: Olsson
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Gran
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Björe
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Fjellström
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Öjvind
authors.initials: Ö
authors.lastname: Davidsson
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Emtenäs
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Dahlén
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Boel
authors.initials: B
authors.lastname: Löfberg
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Zhong-Qing
authors.initials: ZQ
authors.lastname: Yuan
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Sundell
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Cassel
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Jonna
authors.initials: J
authors.lastname: Gyll
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Tommy
authors.initials: T
authors.lastname: Iliefski
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Ågot
authors.initials: Å
authors.lastname: Högberg
authors.affiliation: Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Lindhardt
authors.affiliation: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, SE-431 83, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Malmberg
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D051379:Mice; D023421:Models, Animal; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D054833:Isoindoles; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers
keywords: Atrial fibrillation; IKur; Isoindolinones; Kv1.5; Multicomponent reactions; Structure activity relationship (SAR)